Human CD4 ＋ effector T lymphocytes generated upon TCR engagement with self-peptides respond defectively to IL-7 in their transition to memory cells

The peripheral repertoire of CD4＋ T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4＋ T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4＋ lymphocytes activated by dendritic cells （DCs） presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells （Tmem） from primary effectors activated with mature autologous DCs plus interleukin （IL）-2 （Tmauto）, simulating the circumstances of an active immune response, or allogeneic DCs （Tmallo）. Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors （demonstrated by CD25 downregulation） particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tmauto and TmaHo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tma^o were closely related to conventional memory lymphocytes based on Erk-l/2 activation, whereas Tmauto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD4＋ T lymphocytes recognizing self-peptides in the setting of strong costimulation.

Homeostasis of T Cell Diversity

T cell homeostasis commonly refers to the maintenance of relatively stable T cell numbers in the peripheral lymphoid organs.Among the large numbers of T cells in the periphery,T cells exhibit structural diversity,i.e.,the expression of a diverse repertoire of T cell receptors(TCRs),and functional diversity,i.e.,the presence of T cells at nave,effector,and memory developmental stages.Although the homeostasis of T cell numbers has been extensively studied,investigation of the mechanisms underlying the maintenance of structural and functional diversity of T ceils is still at an early stage.The fundamental feature throughout T cell development is the interaction between the TCR and either self or foreign peptides in association with MHC molecules.In this review,we present evidence showing that homeostasis of T cell number and diversity is mediated through competition for limiting resources. The number of T cells is maintained through competition for limiting cytokines,whereas the diversity of T cells is maintained by competition for self-peptide-MHC complexes.In other words,diversity of the self-peptide repertoire limits the structural(TCR)diversity of a T cell population.We speculate that cognate low affinity self-peptides, acting as weak agonists and antagonists,regulate the homeostasis of T cell diversity whereas non-cognate or null peptides which are extremely abundant for any given TCR,may contribute to the homeostasis of T cell number by providing survival signals.Moreover,self-peptides and cytokines may form specialized niches for the regulation of T cell homeostasis.Cellular & Molecular Immunology.2005;2(1):1-10.