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'It's high time molecular biology became quantitative, it cries out to a physicist ... for modeling. Modeling isn't a crutch, it's the opposite; it's a way of suggesting experiments to do, to fill gaps in your understanding.' John Maddox, Editor of Nature 1966-73, and 1980-95.
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In the last two decades, T cell function has been analyzed in vitro from many different angles, with a great deal of attention dedicated to the basic requirements of activation. During this time, a compendium of information has been collected and has proven to be invaluable. Paradoxically, very little is known about T cell activation and function in vivo. In the last decade, a number of models have been developed which allow the tracking of Ag-activated T cells in vivo and these studies have been instrumental in advancing the field of T cell biology. In particular, a new and emerging paradigm of T cell immunity is evolving.
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BACKGROUND: TS/A cells (a Balb/c-derived tumor cell line), when injected into syngenic mice, give rise to rapidly growing tumors. In this study, a vaccination protocol was established which was able to elicit an immune response effective in controlling tumor growth. MATERIALS AND METHODS: T19.2.1, a TS/A clone enginereed to stably express the mycobacterial cell wall-associated 19-kDa lipoprotein, was used as cell vaccine to immunize Mycobacterium Bovis-BCG pre-immunized Balb/c mice. RESULTS: Mice receiving the two-step vaccination protocol were able to develop a strong anti-TS/A DTH reaction. Moreover, following a challenge with wild-type TS/A cells, some vaccinated animals rejected the tumor and the remaining animals showed a significantly increased survival in respect to controls. CONCLUSION: The expression on TS/A cells of the mycobacterial 19-kDa antigen, recognised in the context of a pre-existing memory immune response, promotes the immunological recognition of the otherwise non-immunogenic wild-type TS/A cells.
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Several methods are now available to evaluate the frequencies of virus-specific CD8 T cells but require a systematic comparison to help at choosing the best strategy for evaluation. First, we compared the ELISpot-IFNgamma assay, intracellular IFNgamma staining and HLA class I tetramer-binding assay to quantify the HIV-specific CD8 T cells. Second, we determined the frequency of recognition of HIV antigens and evaluated whether the mode of antigen presentation might influence the results: We compared HIV antigen presentation in the same ELISpot-IFNgamma assays by using recombinant vaccinia viruses (rVVs) encoding for HIV-LAI Gag, Pol, Env, Nef, Tat and Vif proteins, or a panel of 49 synthetic 8-11 amino acid length peptides tested either individually or pooled. Third, we compared the antigens recognized by memory CTL analysis using chromium release assay (CRA) on CTL lines and by effector CD8 cell analysis using ELISpot assay. Our results show that: (1) Flow cytometry and ELISpot assay measuring IFNgamma production give the same frequency of HIV-specific CD8 T cells; (2) tetramer-binding assay detects more HIV-specific CD8 T cells than other methods; (3) pools of optimal peptides and sum frequencies of individual optimal peptides give similar results in ELISpot assay; (4) ELISpot assays using peptides are more sensitive than those using rVV; and (5) CRA and ELISpot assay when using rVV provide a comparable profile of HIV antigen recognition by memory CTLs (CRA) and effector CTLs (ELISpot) in two thirds cases. These results have important implications for the choice of immunological methods to evaluate CD8 T cells responses to vaccines.
The immunologic consequences resulting from thymectomy in adult life were investigated. Primary humoral responses were not diminished shortly after adult thymectomy, as judged by responses of intact thymectomized mice as well as by the ability of spleen cells from such mice to transfer primary responses. However, secondary humoral responses were substantially reduced in irradiated recipients of spleen cells from primed adult-thymectomized mice, suggesting that the thymus is required in adult life to maintain a population of cells important in the generation of immunologic helper memory. By contrast, small doses of anti-thymocyte serum, which primarily affect recirulating T cells, abrogated the primary humoral response, but allowed the subsequent development of immune memory. Using a technique permitting in vitro sensitization of purified T cells to alloantigens, it was shown that adult thymectomy increases the ability of T cells to generate primary cytotoxic responses, but had little effect upon the development of cytotoxic T memory activity. These experiments suggest that in adult life the thymus maintains a regulatory population of T cells in peripheral tissues which suppress early T cell differentiation to cytotoxic effector cells and potentiates the development of immune memory.
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Suppressor T cells were first described in the early 1970s, but since the hypothetical soluble suppressor factor could not be identified on a molecular level and since appropriate cellular markers were lacking, the suppressor T cell concept vanished for a long time. The discovery by Sakaguchi and co-workers, that the adoptive transfer of CD25+CD4+ -depleted T cells induced several organ-specific autoimmune diseases in immunodeficient recipients, put the suppressor T cell model back into the focus of many immunologists. CD25+CD4+ T cells were named regulatory T cells (Treg) and since then have been intensively characterized by many groups. It has now been well documented in a variety of models that CD25+CD4+ Tregs, in addition to cell-intrinsic peripheral tolerance mechanisms such as anergy induction and peripheral deletion, play indispensable roles in the maintenance of natural self-tolerance, in averting autoimmune responses as well as in controlling inflammatory reactions. However, a number of fundamental questions concerning their origin, mechanism of action, and the sites of suppression remain elusive and are currently a matter of debate. Notably, the potential heterogeneity of Tregs with respect to phenotype and function deserves attention and is a major issue discussed in this review.
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The differentiation state of CD8+ T cells has emerged as a crucial determinant of their ability to respond to tumor and infection. Signals from T-cell receptors, co-stimulatory molecules and cytokine receptors direct the differentiation process. These signals 'program' sustained and heritable gene expression patterns that govern progressive differentiation and lineage commitment. The epigenetic mechanisms by which T cells are programmed are just beginning to be elucidated. Understanding the mechanisms that control CD8+ T-cell differentiation is important in the development of novel immunotherapy strategies.
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To reevaluate whether an association exists between the clinical course of multiple sclerosis (MS) and the activation of memory T cells, we investigated the phenotype of T cells in peripheral blood and cerebrospinal fluid (CSF) of patients with MS using five-color flow cytometry. A cross-sectional study with 39 relapsing-remitting MS patients demonstrated that the percentage of CD25(+)CD45RO(+)CD4(+)CD3(+) cells was significantly increased in peripheral blood as well as in CSF of active MS patients compared with inactive MS patients. A longitudinal study with 11 relapsing-remitting MS patients also showed a higher percentage of CD25(+)CD45RO(+)CD4(+)CD3(+) cells in peripheral blood at the phase of exacerbation than during remission. On the other hand, regardless of the disease activity, the percentage of CD25(+)CD45RO(+)CD8(+)CD3(+) cells in peripheral blood was significantly higher in patients with MS than in healthy control subjects. A lower percentage of CD25(+)CD45RO(+)CD8(+)CD3(+) cells in CSF was observed in active MS patients compared with inactive MS patients. These results suggest that the activation of memory CD4(+) T cells is associated with the exacerbation of MS and activation of memory CD8(+) T cells reflects systemic immunological dysregulation in MS patients. Transient as well as continuous activation of T cells by recall antigens may be involved in the disease course of MS.
Since the 1980s, the occurrence of pertussis cases in developed countries has increased and shifted towards older age groups. This resurgence follows 30 years of intense mass vaccination, and has been attributed primarily to three factors: (1) more effective diagnosis of the disease, (2) waning of vaccine-induced immunity, and (3) loss of vaccine efficacy due to the emergence of new Bordetella pertussis strains. Here we develop and analyse a mathematical model to assess the plausibility of these hypotheses. We consider that exposure to B pertussis through natural infection or vaccination induces an immune response that prevents severe disease but does not fully prevent mild infections. We also assume that these protective effects are temporary due to waning of immunity. These assumptions, describing the mode of action of adaptive immunity, are combined with a standard transmission model. Two distinct epidemiological scenarios are detected: under low transmission, most infections lead to severe disease; under high transmission, mild infections are frequent, boosting clinical immunity and maintaining low levels of severe disease. The two behaviours are separated by a reinfection threshold in transmission. As a result, the highest incidence of severe disease is expected to occur at intermediate transmission intensities--near the reinfection threshold--suggesting that pertussis resurgence may be induced by a reduction in transmission, independently of vaccination. The model is extended to interpret the outcomes of current control measures and explore scenarios for future interventions.
Autoreactive cells that escape from thymic negative selection are either anergized or counter-regulated in the peripheral lymphoid organs by regulatory T (Treg) cells. Most investigated Treg cells are CD4pos cells expressing the alpha chain of the IL-2 receptor (CD25). Absence of this particular population leads to the development of a wide range of autoimmune disorders, suggesting a critical role for CD4pos CD25pos cells in the maintenance of normal immune homeostasis. Numerous studies have aimed at unraveling the mechanisms of regulation, focusing mainly on naturally occurring Treg cells (generated in naive animals) and regulation of CD4pos autoreactive cells. In contrast, generation following antigenic priming of CD4pos CD25pos Treg cells with non-self (viral) antigen specificity and regulation of virus-activated CD4pos and CD8pos cells remain to be investigated. In this review, we describe the data collected over the past few years of intense focus on CD4pos CD25pos Treg cells and present our approach to investigate the generation of antigen-specific Treg cells during the course of an anti-viral immune response.
Plasma cells are cellular factories devoted entirely to the manufacture and export of a single product: soluble immunoglobulin (Ig). As the final mediators of a humoral response, plasma cells play a critical role in adaptive immunity. Although intense effort has been devoted to studying the regulation and requirements for early B cell development, little information has been available on plasma cells. However, more recent work-including studies on genetically altered mice and data from microarray analyses-has begun to identify the regulatory cascades that initiate and maintain the plasma cell phenotype. This review will summarize our current understanding of the molecules that regulate commitment to a plasma cell fate and those that mediate plasma cell function.