Zheng Chen, Ph.D. - US grants

virus; AIDS; immunology; communicable diseases; lymphatic system; biomaterials; Primates; Mammalia;

virus; AIDS; immunology; communicable diseases; lymphatic system; bacteria; Primates; Mammalia;

Co-infection with Mycobacterium tuberculosis and human immunodeficiency virus (HIV) results in high rates of active tuberculosis, and possibly in an acceleration of the progression of AIDS. While the attenuated Mycobacterium bovix Bacille Calmette-Guerin (BCG) has been widely used as a vaccine fro protection against tuberculosis, the recent epidemic of HIV infection has raised serious concerns about its safety in HIV-infected individuals. We have observed a case of disseminated tuberculosis in a rhesus moneky infected with both simian immunodeficiency virus (SIV) and BCG. A rhesus monkey infected for three months with SIVmac was inoculated intravenously with 108 cfu BCG. Five months following BCG inoculation, the monkey developed progressive weight loss, watery diarrhea that did not respond to enrofloxacin, and became moribund. The animal was then euthanized. At necropsy the monkey was found to have chronic adhesive peritonitis, with clear yellowish acites, enlarged mesenteric lymph nodes, thickened small intestines with adherent bowel loops. Histologically small nonnecrotizing granulomas and multinucleated giant cells were diffusely scattered in the lung, liver, spleen, lymph nodes, and mucosa of the small intestines and colon. Marked thymus atrophy and depletion of lymphocytes in the spleen and lymph nodes were evident. This animal also had severe glomerulonephritis. A few acid fast bacilli were seen in macrophages in the mucosa of the small intestines and colon, and in lymph nodes. Molecular diagnostic approaches indicated that the acid fast organisms associated with granulomatous inflammation were Mycobacterium avium or BCG. We have thus demonstrated that a monkey coinfected with SIVmac and BCG developed a fatal dissemination of BCG. This observation suggests that the confection of rhesus monkeys with SIVmac and BCG may produce a useful animal model for exploring the pathogenesis and treatment of tuberculosis in HIV-infected individuals.

A macaque model was employed to explore staphylococcal enterotoxin B (SEB) superantigen-driven T lymphocyte responses. The SEB reactive V + cell subpopulations demonstrated a striking tri-phase response in rhesus monkeys following an SEB challenge in vivo. The hyperacute downregulation, seen as early as two hours through two days after SEB injection, was characterized by a disappearance of the reactive V -restricted PBL subpopulations from the circulation and decreased expression of these cell subpopulations in lymphoid tissues. Following this, a dominant expansion of reactive V -expressing CD4+ cell subpopulations occurred in lymph nodes and spleens, whereas in the peripheral blood a preferential expansion of reactive V -expressing CD8+ cell subpopulations was seen. An exhaustion of this response was then seen, with a prolonged decrease in the number of the reactive V + CD4+ lymphocyte subpopulations. Interestingly, monoclonal or oligoclonal dominance was seen in the reactive V + cell subpopulations in the period of the transition from the polyclonal cellular expansion to the exhaustion of the response, suggesting that some V + cell clones may be more resistant than others to superantigen-mediated depletion. These results indicate that in vivo SEB superantigen-mediated effect on lymphocyte subpopulations in macaques is complex, suggesting that profound dynamics in the TCR repertoires may

Coinfection with HIV and Mycobacterium tuberculosis is associated with high rates of active tuberculosis and possibly an acceleration of the progression to clinical AIDS. Elucidating the interplay of the immunopathogenic events that occur as a result of HIV/M. tuberculosis coinfection is, therefore, of central importance for understanding the immune sequelae of this coinfection. We have shown that macaques coinfected with SIV and Mycobacterium bovis Bacille Calmette-Guerin (BCG) develop a syndrome similar to AIDS-related tuberculosis. Using this SIV/BCG coinfection model, we plan to study the immunopathogenesis of AIDS virus interactions with mycobacteria and the evolution of tuberculosis.

T cells play an important role in triggering the immune rejection of transplanted tissues. Significant efforts have been made to explore the potential for the induction of donor-specific immune tolerance to achieve long-term graft survival without the need for life-long immunosuppressive therapy. Non-human primates are ideal animal models to test the immune-target tolerance for successful allotransplantation. Recent work done in Dr. Judy Thomas' laboratory has shown that the treatment of rhesus monkeys with anti-CD3-Immunotoxin (IT) resulted in profound T cell depletion, and induced stable tolerance without chronic allograft rejection for up to 3 years. While IT protocol clearly facilitates inducing the tolerance of allografts in macaques, important questions remain to be explored regarding fundamental T cell immunology and future application of the IT strategy to cadaveric transplant tolerance induction in humans. Based on the result demonstrating the ability of macaque repertoires in the macaques depleted of T cells can be restored to various degrees through the thymic-dependent and/or-independent pathways. We also hypothesize that alloantigens may drive the dominant T cell response that is relevant to allograft rejection or tolerance. To test these hypothesis, we will: I. Determine restoration of macaque TCR repertoires following T cell depletion. A. Determine restoration of TCR repertoires in juvenile macaques following T cell depletion. B. Determine restoration of TCR repertoires in old macaques following T cell depletion. II. Assess TCR-based thymic output in young and old macaques after T cell depletion. III. Determine the TCR repertoire in rejected kidney allografts of macaque recipients.

DESCRIPTION (provided by applicant): Tuberculosis remains an important life-threatening disease and has recently been declared to be a global health emergency by the World Health Organization. While human CD4 T cells play a crucial role in immune protection against M. tuberculosis infection, other T cell populations are poorly characterized for their roles in immunity to tuberculosis. We have recently demonstrated that memory responses of mycobacterium-specific CDS T cells after M. tuberculosis infection coincided with protection against fatal tuberculosis in BCG-vaccinated monkeys, and that antibody-mediated depletion of CD8 T cells in monkeys with protective memory resulted in the development of severe forms of tuberculosis following M. tuberculosis re-infection by aerosol. Based on these results, we hypothesize that mycobacterium-specific CD8 T cells are an important component of immunity against tuberculosis. In testing this hypothesis, we will answer immune mechanistic questions involving CD8 T cell-mediated anti-tuberculosis immunity. We will: I. Determine the role of CD8 T cells in resistance to primary M. tuberculosis infection. II. Determine the role of CD8 T cells in adaptive immunity to M. tuberculosis re-infection and reactivation tuberculosis. A. Determine the role of CD8 T cells in adaptive immunity against M. tuberculosis re-infection. B. Determine the role of CD8 T cells in controlling reactivation tuberculosis in normal monkeys and SIVmac-infected macaques. III. Determine if vaccine-elicited CD8 T cell responses can confer some protection against tuberculosis in immune competent and SHIV-infected monkeys. A. Examine vaccine-elicited CD8 T cell responses and determine if such immune responses can confer some degree of protection against M. tuberculosis infection in normal monkeys. B. Determine if vaccine-elicited CD8 T cell responses can contribute to immune protection against tuberculosis in SHIV-89.6P-infected monkeys.

DESCRIPTION (provided by applicant): B. anthracis has long been considered a potential biological warfare agent. One of the biodefense research priorities is to develop improved anthrax vaccines. Cell-mediated immune responses may play an important role in vaccine-induced protection against anthrax. Vgamma2Vdelta2 T cells exist only in primates and constitute 60-95% of total human gammadeltaT cell population in the blood. We have recently demonstrated that phosphoantigen-specific Vgamma2Vdelta2 T cells can contribute to adaptive immunity to fatal mycobacterial infection. We have also shown that B. anthracis, like mycobacteria, carries a novel gene encoding GcpE protein that mediates production of phosphoantigen recognized by Vgamma2Vdelta2 T cells. B. anthracis infection of monkeys could prime phosphoantigen-specific Vgamma2Vdelta2 T cells, and result in cross-reactive memory-type responses of these gammadeltaT cells after subsequent infection with phosphoantigen-producing mycobacteria. Since the current anthrax vaccine contains only protein antigens of B. anthracis, phosphoantigen may provide an important addition to anthrax vaccine regimens. We hypothesize that Vgamma2Vdelta2 T cells contribute to both innate and adaptive immune protection against B. anthracis infection. Since peptide-specific CD4 and CD8 T cells may play a role in immunity to anthrax, we further hypothesize that a combined vaccine targeting both phosphoantigen-specific Vgamma2Vdelta2 T cells and peptide-specific CD4 and CD8 T cells are more efficient for immunization and vaccine-induced protection against anthrax. In this R21 application, we will I. Determine vaccine-elicited immune responses of Vgamma2Vdelta2 T cells, and CD4 and CD8 T cells in macaques immunized with a combined vaccine comprised of phosphoantigen and protective antigen (PA) of B. anthracis. II. Determine if combined phosphoantigen and PA immunization of Vgamma2Vdelta2 T cells, CD4 and CD8 T cells can confer protective immunity to inhalation anthrax.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Tuberculosis remains one of the leading public health problems in the world today. HIV epidemic clearly is the most important risk factor. While human CD4 T cells play a crucial role in immune protection against M. tuberculosis infection, other T cell populations are not well characterized for their roles in immunity to tuberculosis. Phosphoantigen-specific V?2Vd2 T cells exist only in primates and constitute 60-95% of total human ?d T cell population in the blood. We have recently demonstrated that macaque V?2Vd2 T cells can mount adaptive immune responses during BCG and M. tuberculosis infections, and that the capacity of memory V?2Vd2 T cells to rapidly expand coincides with immunity to acutely fatal tuberculosis. We therefore hypothesize that V?2Vd2 T cells play a role in immunity to tuberculosis and AIDS-related reactivation tuberculosis. To test this hypothesis, we have adapted macaque models of pulmonary tuberculosis and AIDS-related tuberculosis-like disease. For this project, we will [unreadable] [unreadable] I. Determine if enhanced activation of V?2Vd2 T cells by phosphoantigen treatment during M. tuberculosis infection can attenuate disease course of tuberculosis in immune competent and SIV mac-infected macaques. [unreadable] [unreadable] II. Determine if restored V?2Vd2 T cell responses during antiretroviral therapy or combined antiretroviral-phosphoantigen treatment contribute to protection against SIV-related tuberculosis-like disease or SHIV-induced reactivation tuberculosis. [unreadable] [unreadable] III. Determine the utility of vaccination of V?2Vd2 T cells in delay or prevention of tuberculosis in immune competent and SHIV-infected monkeys. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Biodefense research priorities should include development of immunotherapeutics and effective vaccines against biological warfare agents. Both cellular and humoral immune responses may play a role in immunity to anthrax, plague and tularemia. Vy2V82 T cells exist only in primates and constitute 60-95% of total human y5 T cell population in the blood. We and others have demonstrated that phosphoantigen-specific Vy2V82 T cells can function as both innate and adaptive immune cells, and contribute to adaptive immunity to acutely fatal form of tuberculosis. Our new studies indicate that B. anthracis can indeed produce phosphoantigen stimulating Vy2V52 T cells and prime these cells for cross-reactive memory-type response after subsequent infection with phosphoantigen-producing mycobacteria. Importantly, phosphoantigen HMBPP treatment of monkeys can expand Vy2V52 T cells from <1% to >70% in total circulating T cells. HMBPP-activated Vy2V82 T cells readily migrate to the lung and confer protection against pulmonary mycobacterial infection in macaques. We hypothesize that phosphoantigen HMBPP-mediated activation of Vy2V52 T cells can greatly boost innate and adaptive immune responses to B. anthracis, Y. pestis and F. tularensis, and confer protection against fatal inhalational anthrax, plague and tularemia. We further hypothesize that a combined vaccine comprised of both phosphoantigen and protein antigen can target 4 immune components: Vy2V52 T cells, CD4 T helpers, CDS T killers, and antibodies, and therefore can be more efficient for immunization and vaccine-induced protection against anthrax, plague and tularemia. To facilitate testing these hypotheses, we have worked out clinical and immunological aspects of HMBPP treatment regimens, and developed vaccine platform technology for constructing recombinant BCG and Listeria vaccine vectors. To test our hypothesis and ultimately develop recombinant vaccines against anthrax, plague and tularemia, we will: I. Assess HMBPP regimens for immunotherapeutic effects on fatal inhalational anthrax, plague, and tularemia in nonhuman primates. II. Construct and characterize recombinant BCG and recombinant attenuated Listeria vaccine vectors expressing B. anthrax PA, Y. pestis F1 or F. tularensis Ag. III. Compare oral and intradermal immunization routes for vaccine-elicited immune responses in monkeys that receive heterologous prime-boost vaccination with recombinant BCG and Listeria vaccine vectors expressing B. anthracis PA, Y. pestis F1, or F. tularensis Ag. IV. Determine whether oral heterologous prime-boost vaccination with recombinant BCG and Listeria vaccine vectors expressing PA, F1, or tularemia Ag can confer protective immunity against fatal inhalational anthrax, plague and tularemia in nonhuman primates.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Little is known about the immune distribution and localization of antigen-specific T cells in mucosal interfaces of tissues/organs during infection of humans. In this study, we made use of a macaque model of Mycobacterium tuberculosis infection to assess phosphoantigen-specific VGAMMA2VDELTA2 cells regarding their tissue distribution, anatomical localization, and correlation with the presence or absence of tuberculosis (TB) lesions in lymphoid and nonlymphoid organs/tissues in the progression of severe pulmonary TB. Progression of pulmonary M. tuberculosis infection generated diverse distribution patterns of VGAMMA2VDELTA2 cells, with remarkable accumulation of these cells in lungs, bronchial lymph nodes, spleens, and remote nonlymphoid organs but not in blood. Increased numbers of VGAMMA2VDELTA2 cells in tissues were associated with M. tuberculosis infection but were independent of the severity of TB lesions. In lungs with apparent TB lesions, VGAMMA2VDELTA2 cells were present within TB granulomas. In extrathoracic organs, VGAMMA2VDELTA2 cells were localized in the interstitial compartment of nonlymphoid tissues, and the interstitial localization was present despite the absence of detectable TB lesions. Finally, VGAMMA2VDELTA2 cells accumulated in tissues appeared to possess cytokine production function, since granzyme B was detectable in the Gamma/deltaT cells present within granulomas. Thus, clonally expanded VGAMMA2VDELTA2 cells appeared to undergo trans-endothelial migration, interstitial localization, and granuloma infiltration as immune responses to M. tuberculosis infection.

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (M.tb)-induced tuberculosis (TB) remains the leading morbidity and mortality worldwide, and the magnitude of the problem continues to grow, due in part to HIV pandemics. Sustained increases in cases of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains are making TB extremely difficult to treat and globally control. Since drug resistance is likely to increase, there is a pressed need to develop new vaccines or immunotherapeutics. We have recently shown that IL-2 treatment of macaques can induce remarkable expansion of CD4+CD25(high)Foxp3+ T regulatory cells (Treg) in systemic and respiratory sites, and more importantly confers apparent homeostatic protection against TB lesions. This surprising finding suggests that Treg can function in vivo as homeostatic regulator against TB, far beyond simple inhibition of immune responses. Based on this novel observation, we hypothesize that IL-2-expanded Treg can orchestrate or balance host responses and suppress M.tb-mediated inflammatory events, leading to no or mild TB lesions, whereas IL-2-activated T effector cells producing IFN?;or cytotoxic cytokine may help to limit M.tb replication and dissemination. To test this hypothesis, we will: I. Perform mechanistic studies to determine a critical role of IL-2-expanded Foxp3+ Treg in anti-TB immunity in macaques. II. Determine if intermittent IL-2 treatments during chronic active M.tb infection can sustain Treg expansion, down-regulate TB-driven inflammatory events or associated M.tb replication, and confer immunotherapeutics against severe TB lesions and/or TB cavities. III. Examine kinetics and function of Treg during SHIV-induced reactivation of latent M.tb co-infection, and determine if combined ART and intermittent IL-2 treatment can expand Treg and ?d, CD8 T effector cells, and confer immunotherapeutics against AIDS-related reactivation TB. PUBLIC HEALTH RELEVANCE: This project is proposed based on our recent novel observation that cytokine IL-2 treatment of macaques induces remarkable expansion of CD4+Foxp3+ T regulatory cells (Treg), and confers apparent protection against tuberculosis disease or tissue damages. Studies will elucidate immune mechanisms for IL-2-induced anti-tuberculosis immunity, and explore IL-2-based treatment modalities for tuberculosis and AIDS-related tuberculosis. Findings will exert sustained, long-term impact on tuberculosis research and provide potential alternative treatment for tuberculosis, multi-drug resistant tuberculosis, and AIDS-related tuberculosis.

DESCRIPTION (provided by applicant): While T cells play a role in host defense against Mycobacterium tuberculosis (Mtb) infection, over-reacting T cell responses may contribute to tuberculosis (TB) inflammation and lesions. It is, therefore, important to characterize immune regulation and function of T cell responses in TB. T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) is a membrane protein initially identified as a negative regulator of Th1 cells. However, new studies suggest that Tim-3 expression/ functions in infections appear to be more diverse than previously thought. We have recently found that active TB in macaques and humans remarkably up- regulated Tim-3 expression and that Tim-3+ CD4+/CD8+ T cells displayed polarized effector memory phenotypes. Tim-3+ CD4+/CD8+ T cell subsets showed greater effector functions for producing Th1/Th22/CTL cytokines and for inhibiting intracellular Mtb than Tim-3- T cells. Tim-3+ CD4+/CD8+ T cell subsets are more activated as they expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Silencing of Tim-3 pathway reduced T cell effector function in TB, and stimulation of Tim-3 augmented T effector functions. Our novel findings implicate a new paradigm that Tim-3 signaling facilitates stronger effector functions in active TB patients. We also found that PD-1+ and PD-1- T cells expressed distinct miRNA signatures, and down-regulation of human miRNA miR-31 in PD-1+ T cells enforces stronger effector functions during active TB. Since large numbers of CD4+ and CD8+ T cells express Tim-3 in infections, it is critical to determine whether Tim-3+ CD4+/CD8+ T cells are protective or detrimental, and functional mechanisms. We hypothesize that selected miRNAs help to control or regulate effector functions of Tim-3+ CD4+ and CD8+ T cells in human TB or HIV+TB, and that Tim-3+ T cell effector cells may have double-edge function contributing to both anti-TB immunity and over-reactive immune pathology for TB inflammation and lesions. Our specific aims are: Aim I. Determine if selected miRNAs in Tim-3+ T cells control or regulate effector functions of Tim- 3+ CD4+/CD8+ T cells in active human TB. Aim II. Investigate if selected miRNA signatures in HIV-1 infection potentially depress anti-TB effector functions of Tim-3+ CD4+/CD8+ T cells in HIV+ TB. Aim III. Examine if r-galectin-9 administration during chronic TB can reduce or deplete Tim-3+ CD4+/CD8+ T cells and attenuate immunopathology and TB lesions in macaques. Aim IV. Determine if rapid increases in Tim-3+ T effector cells by adoptive transferring of Tim-3+ T cells during early Mtb infection can confer immune protection against TB in macaques.

DESCRIPTION (provided by applicant): Project Description Tuberculosis (TB) remains one of the major causes of global mortality/morbidity, and has become increasingly prevalent and deadly as a result of HIV/AIDS and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Global control of TB appears difficult because of the lack of an effective protective vaccine and lack of sterilizing drugs. Since drug resistance is likely to increase, there is a pressed need to develop effective vaccine or immunotherapeutic. We have recently made serial novel observations suggesting that V?2V¿2 T cells, the dominant ?¿ T-cell subset in humans/primates, play a role in host response and immune regulation, and contribute to anti-microbial immunity against infections including M. tuberculosis (Mtb). Particularly, we elucidate that Mtb phosphoantigen (E)-4- hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) can associate with APC surface molecule, bind to TCR on V?2V¿2 T cells, and activate/expand V?2V¿2 T cells. Importantly, HMBPP plus IL-2 treatment of macaques induces massive expansion of multi-functional V?2V¿2 T effector cells. HMBPP-expanded V?2V¿2 T effector cells can traffic to and accumulate in airway/lung, produce anti-TB cytokines IFN?/perforin/granulysin, confer anti-TB immunity after Mtb infection and even induce homeostatic protection against fulminating pneumonic plague lesions in lungs. Based on these findings, we hypothesize that V?2V¿2 T cells can function as anti-TB effectors, homeostatic mediators and immune regulators enhancing CD4/CD8 T-cell responses, and confer anti-TB immunity in Mtb infection. To test this hypothesis, we will I. Determine mechanisms by which HMBPP-expanded V?2V?2 T effector cells confer anti- TB immunity. II. Determine whether V?2V¿2 T-cell-targeted treatments during chronic Mtb infection can confer immunotherapeutics against severe TB lesions and/or TB cavities. III. Determine if HMBPP/IL-2 expansion of V?2V¿2 T cells can overcome depressed responses of CD4/CD8 T cells and protect against HIV-related TB in SHIV-infected macaques with low CD4 counts.

DESCRIPTION (provided by applicant): With the rising life expectancy and elderly population in the US, how to achieve healthy aging and extend health span is a pressing biomedical question with profound social ramifications. A pivotal biological mechanism governing our well-being is the circadian clock, the intrinsic timekeeping device that responds to environmental changes and coordinates bodily functions throughout the 24-h cycles. Accumulating evidence has demonstrated a strong correlation between aging and circadian dysfunctions, particularly attenuation of circadian rhythms such as sleep fragmentation and reduced amplitude of body temperature and circulating hormone cycles. We recently identified a unique group of Clock-Enhancing small Molecules, now dubbed as CEMs, via high-throughput screening. To investigate the potential causal role of clock attenuation in aging, we will address the hypothesis that CEMs can improve aged clocks and age-related metabolic decline. We focus on energy metabolism because it is closely regulated by the clock and aging is associated with significant decline in energy utilization. Three Specific Aims are proposed. Specific Aim 1: Determine the clock mechanism of CEMs in aged mice. Using aged PER2::luc reporter mice, we will determine whether CEMs can enhance the bioluminescence rhythm at tissue and single-cell levels. To understand the molecular mechanism, we will systematically characterize the core clock loops in aged tissues, and dissect transcriptional and posttranscriptional mechanisms underlying CEM-mediated enhancement of aged clocks. Specific Aim 2: Delineate the role of CEMs in age-related metabolic decline. We will determine whether CEMs can enhance energy metabolism in naturally aged mice by molecular and physiological approaches. To define the molecular mechanism of CEMs in energy homeostasis of aged mice, we will screen candidate metabolic regulators for altered expression or activity in response to CEM treatment, and investigate the metabolic regulatory mechanisms by CEMs in aged mice. Specific Aim 3: Identify the cellular networks and direct targets of CEMs. To identify both chronic and acute cellular responses to CEMs in aged mice, we will conduct RNA-seq transcriptome profiling using samples from aged mice treated with CEMs for varying periods. To identify direct targets, we will carry out chemoproteomic studies involving affinity pull-down with biotinylated CEM derivatives. Anti-aging roles of specific cellular pathways and proteins from these studies will be further investigated by pharmacological and genetic approaches. Successful completion of these Aims will address the critical question regarding a causal role of clock attenuation during aging and reveal an exciting efficacy of CEMs in prolonging health span.

DESCRIPTION (provided by applicant): The sixth, biennial ?? T Cell Conference will be held on May 16-18, 2014 at the University of Illinois College of Medicine conference center in Chicago, IL. The goals of the conference are to bring together investigators from around the world working in ?? T cell biology to discuss unpublished results, develop new paradigms and directions for future research, highlight and encourage junior investigators, establish collaborations and facilitate sharing of resources. ?? T cells play unique roles in tissue homeostasis, defensive response to infection, tissue repair, inflammation and tumor killing. Recent translational research studies and results from clinical trials demonstrate novel approaches to utilize ?? T cells for immunotherapeutic treatment of patients with a variety of malignancies. The International ?? T Cell Conference is held every 2 years and is the only forum for presentation and discussion of cutting-edge advances in basic to translational work that is focused on ?? T cells. Topics that will be covered in the conference include ?? TCR development and structure, antigens and ligands for ?? T cells, coreceptor and costimulatory molecules for ?? T cell function, specialized roles of ?? T cells in tissue repair and inflammation, function of ?? T cells in malignancy, infectious and autoimmune diseases, and immunotherapy with ?? T cells. Although the majority of the speakers will be selected from abstracts, commitments for participation have been obtained from the organizing committee, session chairs, discussion leaders and key speakers who are leaders in the field including women, minorities, and junior investigators. Funds are requested to provide support for travel awards for trainees and rental fees for conference space, poster displays, audio visual equipment and technical assistance.

? DESCRIPTION (provided by applicant): Tuberculosis(TB) remains one of major causes of global mortality due to HIV/AIDS and multidrug-resistant TB (MDR-TB). Global control of TB is difficult because of the lack of an effective protective vaccine and sterilizing drugs. Since drug resistance likely increases, there i a pressed need to develop new vaccine or immuno- therapeutic. However, there is road-block for vaccine/therapeutic efforts since immune components of anti-TB immunity remain unknown in humans, and in-depth studies are needed to understand how HIV precisely destructs protective mechanisms leading to enhanced TB susceptibility and severity. Our decades-long studies elucidate multi-functional roles for Mtb-specific V?2V?2 T cells, the cell subset existin only in primates. Our new studies provide 1st evidence that dominant V?2V?2 T cells are protective, as they act very fast, traffic to lung within hours and confer anti-TB immunity. In addition, primate CD8+ T cells play a critical role in anti-TB immunity, and CD4+ T cells can function as innate-like cells to control very early TB dissemination while adaptively containing TB progression & sustaining multi-effector functions of CD8+ T and CD3- lymphocytes. We also show that human/macaque Th22 cells can carry membrane-bound IL-22 after de novo production and inhibit intracellular Mtb. Mechanically, rapid pulmonary trafficking/accumulation of vaccine-elicited CD4+/CD8+ Th1 clones appears to be a mechanism underlying T-cell-mediated protection against TB. This principle is supported further by our paralleled studies indicating that IL-2 administration during innate phase of Mtb infection rapidly expands pulmonary CD4+/CD8+ T effectors and confers anti-TB immunity. Furthermore, we showed that co-infection with AIDS virus and mycobacterium reduces the ability of innate/adaptive T cells to traffic/accumulate in the pulmonary compartment leading to enhanced susceptibility to HIV-related TB and reactivation. Notably, our collaborators for this project have exceptional track records of innate-like human CD1b-restricted T cells (22) and human innate immunity including VitD-induced anti-TB immunity, respectively. Our series of novel findings provide strong rationale to investigate immune mechanisms by which innate/adaptive components confer anti-TB immunity in immune competent and HIV-1-infected humans. We hypothesize that fast-acting innate T-cell populations can rapidly traffic to lung upon Mtb exposure, contain Mtb infection and bridge or synergize VitD-IL-32 innate immunity or adaptive T cells to sterilize Mtb and that HIV infection destructs these protective components. To test this hypothesis, we will recruit crucial human cohorts. Importantly, we will confirm human findings in relevant macaque TB and HIV+TB models. A success of this project will provide new concepts and mechanisms conceiving how the human host mounts sterilizing immunity against Mtb infection and how HIV destructs the sterilizing mechanisms.

The project focuses on swarming cyber-physical systems (swarming CPS) consisting of a collection of mobile networked agents, each of which has sensing, computing, communication, and locomotion capabilities, and that have a wide range of civilian and military applications. Different from conventional static CPS, swarming CPS rely on mobile computing entities, e.g., robots, which collaboratively interact with phenomena of interest at different physical locations. This unique feature calls for novel sensing-motion co-design solutions to accomplish a variety of increasingly complex missions. Towards this, the overall research objective of this project is to establish and demonstrate a generic motion-sensing co-design procedure that will significantly reduce the complexity of the mission design for swarming CPS, and greatly facilitate the development of effective, efficient and adaptive control and sensing strategies under various environment uncertainties. This project aims to offer comprehensive scientific understanding of the dynamic nature of swarming CPS, contribute to generic engineering principles for designing collaborative control and sensing algorithms, and advance the enabling technologies of practically applying CPS in the challenging environment. The research solutions of this project aim to bring significant advance in the environmental sustainability, homeland security, and human well-being. The project provides unique interdisciplinary training opportunities for graduate and undergraduate students through both research work and related courses that the PIs will develop and offer.

The project significantly advances the state of the art in cooperative control and sensing and provide an enabling technology for swarming CPS through highly interrelated thrusts: (1) a generic sensing and motion co-design procedure, which reveals the fundamental interplay between the sensing dynamics and motion dynamics of swarming CPS, will be proposed to facilitate the development of effective and efficient control and sensing strategies; (2) by following such co-design procedure, provable correct, computation efficient, and communication light control and sensing strategies will be developed for swarming CPS with constrained resources to accomplish specific missions, e.g., locating pollutants, in an unknown field, while navigating through uncertain spaces; (3) to provide an enabling mobile platform to verify the proposed strategies, innovative small, highly 3D maneuverable, noiseless, energy-efficient, and robust robotic fish fully actuated by smart material will be designed to meet the maneuvering requirements of the proposed algorithms; (4) novel Magnetic Induction (MI)-based underwater communication and localization solutions will be developed, which allows robotic fish to timely and reliably exchange messages, while simultaneously providing accurate inter-fish localization in the harsh 3D underwater environment; and (5) the proposed sensing-motion co-design strategies will be verified and demonstrated using a school of wirelessly interconnected robotic fish in both lab-based experiments and field experiments.

This Faculty Early Career Development (CAREER) project has the main goal of realizing artificial muscle with mechanical and dynamic properties similar to natural muscle. In particular, this project considers the use of a class of materials called dielectric elastomers (DEs) that have compliance, resilience, and force per area comparable to biological muscles. Like biological muscles, these materials can be self-sensing, allowing precise control of contraction or extension without needing visual feedback or other auxiliary sensing schemes. The ultimate goal of the project is to achieve dexterous, lightweight, and energy-efficient prostheses using DE-based artificial muscles, in contrast to the heavy and inefficient electric motors of the current generation of robotic arms. The project incorporates aspects of bio-inspired design, device fabrication, and dynamic modeling, sensing, and control. The success of this project will help provide affordable, reliable, and comfortable prostheses to the estimated two million military veterans and civilians who have lost hands, arms, or legs to accidents, natural disasters, wars, diseases, or aging. This project will also train the next-generation workforce with skills in the dynamic modeling, control, and fabrication of devices based on smart materials and structures. Activities to attract students to this area of research will improve enrollment in science, technology, engineering, and mathematics (STEM) disciplines.

The long-term goal of this research is to develop lightweight, compliant, and self-sensing DEs to emulate the actuation and sensing of biological muscles for robotic assistive applications. A first step towards this goal is to obtain bio-inspired design, modeling, self-sensing, and control strategies for DE actuators in a prosthetic hand application. This project will emphasize the following core goals: 1) create a novel artificial muscle structure consisting of a tubular DE artificial muscle attached to carbon fiber artificial tendons; 2) derive a low-order physics-based model capturing the nonlinear elasticity and strain-dependent electrical impedance of the DE actuator; (3) implement a sensitive and robust nonlinear state observer using actuator self-sensing of the strain-dependent electrical impedance; (4) derive a state-boundary avoidance control strategy to protect the DE actuator from damage; and (5) build a DE-enabled prosthetic hand to demonstrate dexterous manipulation with efficient, and compliant actuation.