Lymphocyte numbers are regulated both by responses to conventional exogenous antigens and endogenous microflora, by stimulation by self-peptide/MHC complexes and by the action of a series of cytokines. This multifaceted regulation permits individuals to maintain a broad repertoire of lymphocytes of distinctive specificities, allowing responses against a vast array of foreign substances and, at the same time, providing a pattern of memory based on the immunization history of the individual. The study of the process of lymphocyte dynamics that underlies this regulation requires a multidisciplinary approach, aimed both at the molecular underpinnings of the processes through which lymphocytes survive and proliferate and a systems/ computational biology approach to appreciate the overall mechanisms governing total numbers of lymphocytes of distinct phenotype and distinct specificity. Emphasis has been placed on four aspects of this problem: the priming, expansion and differentiated phenotype of naive CD4 T cells in response to antigen challenge, the dynamics of lymphocyte memory and of memory phenotype cells, the mechanisms underlying CD4 T cell depletion in HIV infection, and the process of homeostatic proliferation and death. In an effort to develop strategies to enhance response of nave and memory cells to their cognate antigens, it was observed that the most potent stimulant of such expansion was the cytokine IL-1. When expansion of CD4 TCR transgenic T cells in a syngeneic host in response to antigen was measured, it was found that administering IL-1 over a 3 to 5 day period caused a ten-fold or greater enhancement in the degree of expansion when compared to that seen using conventional adjuvants such as LPS. This was equally true for naive and memory cells and was not mediated by other cytokines. The use of recipients that were IL-1 receptor knockouts and IL-1 receptor-sufficient donors of TCR transgenic T cells showed that IL-1 could act directly on the responding CD4 or CD8 T cells to mediate expansion. IL-1 receptor antagonist diminished the adjuvant effect of LPS indicating that a substantial portion of the effect of this conventional adjuvant was due to endogenous production of IL-1. The very robust effect of IL-1 suggests it may have a role in certain immunization strategies. IL-1 acts directly on CD4 T cells to enhance their differentiation into IL-17 producing cells. However, although IL-1 acts directly on CD8 cells to mediate their expansion, differentiation of CD8 into efficient cytotoxic cells requires the action of IL-1 on non-T cells. IL-1 strikingly enhances the frequency of effector/memory CD8 T cells that migrate into peripheral tissues such as lung and liver. Such migration requires expression of IL-1R1 on a cell other than the responding T cells. Strikingly, the effects of IL-1 during priming are retained at the time of secondary challenge even though IL-1 is not administered again. Thus, the secondary response in mice primed in the presence of IL-1 includes increased in numbers of antigen-specific effector CD8 T cells, a greater presence in the tissues, and the expression of large amounts of granzyme B. Unexpectedly, IL-1-driven granzyme B induction of CD8 T cells is primarily mediated by vascular endothelial cells, a conclusion that was supported by co-culture experiments showing that IL-1 signals HUVEC cells, which in turn increase the number of granzyme B+ CD8 T cells. These findings suggest that expansion and effector differentiation of CD8 T cells are differentially regulated by IL-1. Moreover, preliminary experiments also showed that IL-1 administration increases the antitumor activity of CD8 T cells against B16 melanoma cells. Memory CD4 T cell proliferation was shown to be quite slow. Specific T cells from mice infected with LCMV divide at a rate of <2% per day. By contrast CD44bright CD25- CD4 T cells divide much more rapidly, at 8 to 10% per day. This rapid steady state proliferation of memory phenotype CD4 T cells is similar in conventional and germfree mice. Analysis of the repertoire of memory phenotype undergoing proliferation revealed no difference in receptor complexity from that of non-dividing memory phenotype cells. This implies that division is largely stochastic and probably dominantly driven by cytokines or other endogenous ligands rather than by peptide/ MHC complexes, whether of exogenous or endogenous origin. An important question is the role these cells might play in host defense. Is their generation and development into effector cells an irrelevant consequence of how the immune system has evolved or do these cells contribute to pathogen resistance by providing a form of innate-like immunity? Recent studies suggest that the latter is the case. Memory phenotype and authentic memory cells differ from one another not only in their proliferative rates but, based on an RNA-SEQ analysis, also on the expression of NUR77, the latter being highly expressed on authentic memory cells even 30 days after priming, when they are already quiescent. Interestingly, in neonatal mice, the memory phenotype pool is efficiently colonized and preliminary results suggest that after 2 weeks of age, thymic emigrants enter the pool very inefficiently. We suspect then that the memory phenotype pool represents a set of self-specific cells generated early in the life of the individual and capable of producing Th1, Th2 or Th17 type cytokines early in infections as a results of stimulation of these cells through key cytokines, self-peptide MHC complexes or a combination of the two. In a sense, these cells are adaptive Th cells with a potent innate functionality CD4+ T cells are composed of nave, pathogen-specific memory, and pathogen-independent memory-phenotype (MP) cells. Nave and pathogen-specific memory cells play key roles in adaptive immune responses to primary and secondary infections, respectively. By contrast, MP cells are known to develop independently of foreign antigens but the homeostatic mechanisms regulating their generation and maintenance as well as their biological functions are unclear. Previously we had shown that MP cells are generated from nave cells not only in lymphopenic but also in lymphoreplete environments, dependently of TCR signaling induced by available pMHC ligands including self antigens and CD28 signaling. Once generated, these MP cells became less dependent upon TCR signaling but still required CD28 for their proliferation. Interestingly, these MP cells seemed to have innate-like function; they produced IFN- at a very early time point of Toxoplasma infection (as early as day 2 post infection). To address the mechanisms of this innate-like function, in this year we examined the IFN- production by MP cells in more details. We firstly confirmed that MP cells but not Ag-specific effector cells derived from nave cells produce IFN- even when TCR signaling is blocked by Y3P antibody or cyclosporine A during infection. This IFN- production was almost exclusively seen in T-bet hi but not in T-bet lo MP cells, was dependent upon IL-12 and further promoted by IL-18. Furthermore, MP cells could significantly prolong survival of T. gondii-infected Rag c KO mice, especially in the presence of IL-12, suggesting the biological importance of this innate-like cell population. Further investigation will establish how MP cells exert their function in the periphery, which may lead to development of novel therapeutic strategy toward Th1-related infectious and inflammatory diseases.
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