Naive CD4+ T cells activated through TCR/CD28 under Th1 or Th2 conditions expressed canonical cytokine patterns irrespective of cell division. Only cells that had divided fewer than four times were capable of reexpressing alternative cytokines when restimulated under opposing conditions. Although T cells transcribed both IFN-gamma and IL-4 within hours in a Stat4-/Stat6-independent manner, neither T-bet nor GATA-3 was induced optimally without Stat signals, and polarized cytokine expression was not sustained. Cytokine genes were positioned apart from heterochromatin in resting T cell nuclei, consistent with rapid expression. After polarization, the majority of silenced cytokine alleles were repositioned to heterochromatin. Naive T cells transit through sequential stages of cytokine activation, commitment, silencing, and physical stabilization during polarization into differentiated effector subsets.

The diverse response of individuals within populations to infectious pathogens remains poorly understood, although genetic determinants undoubtedly contribute in substantial ways to the outcome of infection. In a mouse model of infection with the intramacrophage protozoan Leishmania major, susceptibility correlates both with aberrant helper T cell differentiation biased towards the production of interleukin 4 and with the presence of an endogenous CD4 T cell repertoire that recognizes an immunodominant parasite antigen with high frequency. In the setting of the particular ecological niche occupied by Leishmania, this combination of otherwise unrelated factors synergizes to result in exquisite susceptibility to this single pathogen, without seemingly compromising host defenses against other agents. Similar paradigms could underlie susceptibility to other pathogenic organisms.The ratio of asymptomatic to symptomatic cases is characterhave begun to identify areas linked to control of disease [2 -6], we have adopted approaches that target the extensive insights istically large for most infectious organisms. As assessed by a variety of humoral or cellular assays, large numbers of persons regarding the immunology of disease susceptibility to this organism. have mounted host responses to pathogens without overt or recognizable disease in the past. Although microbial factors, including such things as virulence determinants, inocula, and CD4 T Cell Subsets and Disease Susceptibility routes of exposure, undoubtedly affect the subsequent manifestations of infection, host factors are a substantial contributor Shortly after the report that stable mouse CD4 T cell clones to the outcome. The enhanced prevalence of infectious diseases could be divided into subsets defined by the cytokines they among newborns and the aged underscores the importance of produced (reviewed in [7]), the L. major model was used to general determinants of host immunity. Less understood are demonstrate the occurrence of these subsets in vivo. Resistance the mechanisms by which unknown genes might together result was associated with the appearance in the draining lymph nodes in enhanced susceptibility in a given individual to unique orof parasite-specific type 1, or Th1, cells -CD4 effector T cells ganisms that survive advantageously in that host. Animal modthat released interferon-g (IFN-g) and lymphotoxin after stimels provide one way to identify susceptibility genes that might ulation. Conversely, susceptibility in BALB/c mice was associbe used to screen human populations to ascertain their contribuated with the appearance of type 2, or Th2, cells -CD4 effector tions to human disease and, ultimately, to identify patients at T cells that released interleukin-4 (IL-4) (reviewed in [1]). high risk for disease and/or potential molecular targets for Subsequent work in a number of systems demonstrated that therapy.Th1 cells were required for activation of phagocyte-dependent Inbred mice, because they contain a fixed genome, provide immunity, consistent wit...

Activation of naive Th lymphocytes by the TCR and the costimulatory molecule, CD28, is believed to provide competent signals for differentiation to effector cells. Such activated cells proliferated and expressed IL-2, but arrested in an immature state maintained by CTLA-4. Although unresponsive to restimulation by TCR/CD28 alone, restimulation with TCR/CD28 and either Stat4- or Stat6-mediated cytokine signals rescued cells to proliferate and differentiate to the appropriately matched canonical Th subsets. Addition of IL-4 at defined periods revealed that naive T cells were receptive to IL-4-mediated differentiation for up to 3 days after their initial priming. A Stat-dependent anergic checkpoint between clonal expansion and effector cell differentiation may defer the cytokine profile to be instructed at the site of infection, thus preventing the unregulated development of potentially damaging effector cells.