Richard P. Ciavarra - US grants

A virus specific cytotoxic thymus (T)-derived lymphocyte (CTL) response is composed of two major components; 1) an afferent (inductive) phase where antigen triggered CTL precursors (CTL-P) clonally expand and differentiate into effector cells and 2) an efferent phase where effector function (cytotoxicity) presumably mediates a protective role for the virus-infected host. At the effector cell stage, lytic activity is triggered following T cell receptor binding of extrinsic (viral) antigen. However, this event is deceptively complex and the sequelae leading to the expression of lytic activity remain obscure. Therefore, my first objective is to address two questions concerning events which are thought to be important in triggering anti-viral CTL activity; namely, 1) is insertion of viral antigens into the target cell plasma membrane an obligatory step in the generation of CTL target antigens and 2) are viral and H-2 antigens co-capped during CTL/target interaction? My second objective will focus on identifying and characterizing T cell derived inductive signals required for the generation of anti-viral CTL responses in vitro. More specifically, I will characterize T cell signals (both helper and suppressor) triggered during an anti-viral CTL response as well as test the hypothesis that memory CTLs possess a different maturational pathway than CTL-P. Both responder and nonresponder mouse strains will be evaluated in order to gain insights into the cellular basis of nonresponsiveness. The proposed studies will be performed using a simple, antigenically well defined virus system, vesicular stomatitis virus (VSV).

Studies in ectothermic animals have demonstrated that behaviourly-induced fever is associated with increased survival following challenge with a number of pathogenic agents. This and other observations suggest that fever may increase host survival by augmenting acquired immunity; thus, the fever response, which is notably conserved throughout evolution, may be beneficial to the host. We will test this hypothesis by evaluating the effect of febrile temperatures on cytotoxic thymus (T)-derived (CTL) responses, an effector population believed to be important in host defense. Evidence is presented that lymphocytes are extremely sensitive to temperature since 1) very slight elevations in temperature induce lymphocyte stress proteins and 2) febrile temperatures (39 degrees C) inhibit the generation of Sendai Virus (SV) specific CTL responses. We will extend our studies on the role of febrile temperatures on SV CTL responses by 1) testing the generality of this observation and 2) determine the mechanism of temperature-dependent inhibition. Fever studies will be performed in vivo to compare thermosensitive events detected during in vitro and in vivo CTL maturation. Since the immune system generally must function in the presence of stress (e.g. fever, circulating glucocorticoids), it is important to determine how various stressors modify lymphocyte biology and immune competence. We will therefore characterize the lymphocyte stress protein response following exposure to a number of putative stressors (temperature, heavy metals, glucocorticoids). CTL responses will then be analyzed in control and stress-tolerant lymphocytes either in the absence or presence of the same or different stressor. In this way we will determine whether lymphocyte stress proteins (or the stress-tolerant state) alter these responses and/or serve to protect immune function in the presence of a stressor. It is expected that these studies will provide new information on the relationship between stress, stress proteins and T cell function.