Homeostatic expansion and phenotypic conversion of naïve T cells in response to self peptide/MHC ligands

Abstract

Recent data suggest that survival of resting, naïve T cells requires an interaction with self MHC molecules. From analysis of the class I MHC-restricted T cell receptor transgenic strain OT-I, we report a different response. Rather than merely surviving, these T cells proliferated slowly after transfer into T-depleted syngeneic hosts. This expansion required both T cell ''space'' and expression of normal levels of self class I MHC molecules. Furthermore, we demonstrate that during homeostatic expansion in a suitable environment, naïve phenotype (CD44 low ) OT-I T cells converted to memory phenotype (CD44 med/high ), despite the absence of foreign antigenic stimulation. On the other hand, cells undergoing homeostatic expansion did not acquire cytolytic effector function. The significance of these data for reactivity of T cells with self peptide͞ MHC ligands and the implications for normal and abnormal T cell homeostasis are discussed. During thymic development, T cells require an interaction of their clone-specific T cell receptor (TCR) with self peptide͞ MHC ligands to survive the process of positive selection (1). Once T cell maturation is complete, however, it has been assumed that such reactivity toward self is lost (inherent in the idea of self tolerance) and that the TCR played no significant role in the survival of resting naïve T cells, before encounter with foreign antigen. This image of the TCR playing the role of ''Sleeping Beauty,'' waiting for the appropriate peptide͞MHC ligand to activate the T cell from its rest, has been challenged by recent data suggesting a ''Red Queen'' analogy is closer to the mark, i.e., that naïve T cells require a constant engagement of the TCR with self ligands simply to persist in an quiescent state (2, 3). Thus, together with a pivotal role for certain cytokines (4), TCR interactions with self may be critical for maintenance of the naïve T cell population.The most extensive analysis of this phenomena involved adoptive transfer of T cells bearing the anti-H-Y͞D b TCR transgene (H-Y TCR) into irradiated hosts (5). These studies showed that naïve CD8 T cells survived for long periods of time in the presence of cognate self MHC molecules (i.e., in that case, H-2D b ) and persisted as resting cells in the absence of stimulatory antigen. These same cells disappeared from the secondary lymphoid tissue in the absence of this class I MHC molecule, even if another class I molecule (K b ) was present, suggesting a correlation between survival and TCR recognition of self. Different rules applied to memory H-Y TCR transgenic T cells, which required expression of class I MHC to survive and proliferate but did not distinguish the presence of cognate or noncognate class I (5). Similar conclusions have been drawn by other groups concerning a homeostatic interaction of CD4 and CD8 T cells with self class II and class I MHC molecules, respectively (6-14). Those studies concluded that naïve T cells require TCR interactions with self to survive.We sought to extend these findings by usin...

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

“…Naive T cells that undergo homeostatic proliferation in lymphopenic mice, a process that involves TCR recognition of specific self-peptide/MHC complexes, differentiate directly into memory cells and acquire phenotypic and functional characteristics of antigen-induced memory T cells (17,(32)(33)(34)(35). Thus, the maintenance of a naïve phenotype by TCR-tg cells following CTLA4Ig treatment may simply reflect an inhibition of homeostatic proliferation.…”

IFN-γ Receptor Signaling Regulates Memory CD8+ T Cell Differentiation

“…Under lymphopenic conditions, the recognition of self-peptide-MHC complexes is sufficient to activate naive CD8 + T cells and induce their LIP and subsequent differentiation into IFN-g-producing memory-like cells (3)(4)(5)(6)(7)(8). In lymphopenic mice, innate immune cells produce IFN-g in response to the commensal microflora (24).…”

“…In the following contraction phase, most effector CD8 + T cells die; few cells survive to form a long-lived memory pool (1,2). However, under lymphopenic conditions, low-affinity self-peptide-MHC complexes are sufficient to trigger CD8 + T cell activation, lymphopenia-induced proliferation (LIP), and subsequent differentiation into memory-like cells (3)(4)(5)(6)(7)(8). Importantly, the comparison of their gene-expression profiles suggests that the molecular pathways guiding the differentiation of LIP-and cAg-induced memory are redundant (9).…”

Differential Survival of Naive CD4 and CD8 T Cells

“…This could be a consequence of recognition of bona fide Ag due to expression of additional TCRs in Rag ϩ donors or because some T cells are activated under these conditions by cross-reactive Ags present in the adoptive host (17,32). This might more easily happen for TCR with high avidity, which can interact with a wide range of selection/survival ligands such as the AND TCR (22,26) …”