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 systemics/ 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 and expansion 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. Unit scientists have shown that primary responses are highly dependent upon the number of precursor cells that can respond to antigenic challenge. Using both real time PCR and flow cytometric analysis to measure the response when TCR transgenic cells are transferred to intact recipients, it has been shown that the factor of expansion (FE) of the antigen-stimulated CD4 T cells is highly dependent upon the number of specific precursors. In a model system based on responses of T cell receptor transgenic cells specific for a cyctochrome C peptide, when the frequency of precursors in the recipient is 3 or less, FE is 1500, at 300 cells it is 200 and at 30,000 it is 20. Limitation in expansion does not result from a smaller fraction of cells responding but rather, at least in part, from diminished proliferative rates of responding cells. Diminution in FE as number of precursors increase cannot be accounted for by Fas, TNF or IFNg-mediated cell death nor can it be due to limitation in numbers of dendritic cells or in amounts of antigen as increasing either DC number or amount of antigen does not alter the relationship of FE and precursor number. Furthermore, the effect is not altered by supplementation with IL-1, IL-2, IL-7 or IL-15. The relative frequency of regulatory T cells, either derived from the responding cells or from the host, is not altered by precursor frequency and the difference in FE occurs even when responding cells are unable to develop into regulatory T cells. The effect is highly antigen specific in that large numbers of cells of one specificity do not effect the rate of expansion of small numbers of cells of another specificity. In collaboration with Professor Gennady Bocharov of the Russian Academy of Sciences, a mathematical model of the proliferation of these cells has been developed conforms very well to the observed data. In the course of analyzing the control of FE on the part of both nave and memory cells, it was observed that the most potent stimulant of FE 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 enhancement in FE 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 effect could only be partially explained by enhanced proliferation so that greater survival was also implicated. 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. The 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. Initial analysis of genes activated and suppressed in cells responding to antigen in the presence of LPS suggest avenues for further analysis that may lead to a mechanistic understanding of the IL-1 effect. 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 cells requires the action of IL-1 on non T cells. Strikingly, the effects of IL-1 during priming are retained at the time of secondary challnege even though IL-1 is not administered again. Thus, the secondary response in mice primed in the presence of IL-1 includes CD8 cells increased in number, found in the tissues, and siaplying a high degree of granzyme B expression and IFN gamma production. Experiments involving the use weak vaccines, such as heat killed Listeria monocytogenes, the gD2 protein of H. simplex, heat killed Blastomyces or peptides associated with vaccinia, result in strikingly induced protection if IL-1 is included in the priming regimen. 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. Furthermore 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 rather than by peptide/ MHC complexes, whether of exogenous or endogenous origin. Memory phenbotype and autehntic memory cells differ from one another not only in their proliferative rates but, based onan 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. Efforts to understand the role of distinct priming regimens to induce particular phenotypic CD4 T cells responses to lung immunization reveal a profound effect of different """"""""adjuvants"""""""". Priming in the presence of LPS leads to a TH17 response whereas priming in the presence of polyI:C to an exclusive IFNgamma response. Based on studies with KO mice, the results have been interpreted as indicated that LPS, through its activation of Myd88, results in robust IL-10 production, blocking IL-12 production and Th1 priming. In parallel, though its activation of TRIF/TRAM, it activates IL-1 production, markedly enhancing Th17 priming. By contrast, polyI:C, acting through TLR3 and TRIF activates type I intewrferon and IL-12, enhancing IFNgamma priming and blocking Th17 induction. These results give important insight into the precise resultation of CD4 T cells responses to distinct pathogens in the lung.
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