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. The advantage of smaller cell numbers is even greater oif the cells are unresponsive to IL-27, suggesting that lymphocyte expansion is innately independent of precursor number but that effect is tempered by feedback effects of IL-27. 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. Experiments involving the use weak vaccines, such as heat killed Listeria monocytogenes, the gD2 protein of H. simplex, heat killed Blastomyces or a pneumococcal protein candidate have shown that the magnitude and protective value of these agents is strikingly enhanced when IL-1 is used together with the vaccine to enhance immunogenicity. 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. Working with colleagues at the Oregon Regional Primate Center, we have analyzed lymphocyte dynamics in SIV-infected macaques and have obtained evidence for CD4 T cell populations that decay at very distinct rates in the period after their burst-like expansion. Laboratory of Immunology scientists and our colleagues have shown the critical role that aberrant immune activation in lentiviral infection plays in the decay of CD4 T cell number and in the degradation of immunocompetence in SIV-infected macaques and HIV-infected humans. The ongoing activation of the immune system caused directly or indirectly by infection appears to be of particular importance in the loss of potential effector cells during the chronic phase of the infection.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2011
Total Cost
$1,291,699
Indirect Cost
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State
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Caucheteux, S M; Hu-Li, J; Mohammed, R N et al. (2017) Cytokine regulation of lung Th17 response to airway immunization using LPS adjuvant. Mucosal Immunol 10:361-372
Guo, Liying; Huang, Yuefeng; Chen, Xi et al. (2015) Innate immunological function of TH2 cells in vivo. Nat Immunol 16:1051-9
Paul, William; Neill, Ushma S (2015) A conversation with Bill Paul. J Clin Invest 125:1367-8
Helmstetter, Caroline; Flossdorf, Michael; Peine, Michael et al. (2015) Individual T helper cells have a quantitative cytokine memory. Immunity 42:108-22
Grossman, Zvi; Paul, William E (2015) Dynamic tuning of lymphocytes: physiological basis, mechanisms, and function. Annu Rev Immunol 33:677-713
Paul, William E (2014) Endless fascination. Annu Rev Immunol 32:1-24
Paul, William E; Grossman, Zvi (2014) Pathogen-sensing and regulatory T cells: integrated regulators of immune responses. Cancer Immunol Res 2:503-9
Yamane, Hidehiro; Paul, William E (2013) Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets. Immunol Rev 252:12-23
Paul, William E; Milner, Joshua D; Grossman, Zvi (2013) Pathogen-sensing, regulatory T cells, and responsiveness-tuning collectively regulate foreign- and self-antigen mediated T-cell responses. Cold Spring Harb Symp Quant Biol 78:265-76
Roediger, Ben; Kyle, Ryan; Yip, Kwok Ho et al. (2013) Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol 14:564-73

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