ABSTRACT
Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8+ T cells and self-renewal of central-memory CD8+ T cells. We now show that T-bet represses transcription of IL-7Ralpha and drives differentiation of effector and effector-memory CD8+ T cells at the expense of central-memory cells. We also found T-bet to be overexpressed in CD8+ T cells that differentiated in the absence of CD4+ T cell help, a condition that is associated with defective central-memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of "unhelped" memory CD8+ T cells. T-bet, thus, appears to function as a molecular switch between central- and effector-memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8+ T cells.
Subject(s)
CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation , Immunologic Memory/immunology , T-Box Domain Proteins/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Interleukin-7 Receptor alpha Subunit/metabolism , Mice , Repressor Proteins/metabolism , T-Box Domain Proteins/deficiencyABSTRACT
Memory CD8 T cells, unlike their naive precursors, are capable of rapidly producing high levels of cytokines, killing target cells, and proliferating into numerous secondary effectors immediately upon Ag encounter. This ready-to-respond state contributes to their superior ability to confer protective immunity, yet the underlying molecular basis remains unknown. In this study, we show that memory CD8 T cells have increased histone acetylation compared with naive CD8 T cells; however, those activated without CD4 T cell help ("unhelped") remain hypoacetylated and fail to develop into functional, protective memory. Treatment with a histone deacetylase inhibitor during activation results in increased histone acetylation in unhelped CD8 T cells and restores their ability to differentiate into functional memory cells capable of immediate cytokine production and providing protective immunity. These results demonstrate that CD4 T help-dependent chromatin remodeling provides a molecular basis for the enhanced responsiveness of memory CD8 T cells.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Chromatin Assembly and Disassembly , Histone Deacetylases/metabolism , Immunologic Memory , Acetylation , Animals , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Chromatin Assembly and Disassembly/drug effects , Enzyme Inhibitors/pharmacology , Female , Histones/metabolism , Hydroxamic Acids/pharmacology , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Protein Synthesis Inhibitors/pharmacologyABSTRACT
Generating long-lasting, protective CD8(+) T-cell memory via vaccination is critical for combating infectious diseases. Advances in the past year have provided many new insights into how memory CD8(+) T cells are generated. It is now recognized that CD8(+) T cells differentiate from 'effector memory' cells into 'central memory' cells, which are stably maintained and confer superior protective immunity. Furthermore, CD4(+) T-cell help plays an important role in guiding the differentiation of CD8(+) T cells into long-lasting, functional memory. These findings have important implications for developing vaccine strategies that induce high-quality CD8(+) T-cell memory, not just high quantity.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Communicable Diseases/immunology , Immunologic Memory , Vaccination , Animals , Cell Differentiation/immunology , HumansABSTRACT
Memory T cells (T(M)) are able to rapidly exert effector functions, including immediate effector cytokine production upon re-encounter with Ag, which is critical for protective immunity. Furthermore, this poised state is maintained as T(M) undergo homeostatic proliferation over time. We examined the molecular basis underlying this enhanced functional capacity in CD8 T(M) by comparing them to defective CD8 T(M) generated in the absence of CD4 T cells. Unhelped CD8 T(M) are defective in many functions, including the immediate expression of cytokines, such as IL-2 and IFN-gamma. Our data show that this defect in IL-2 and IFN-gamma production is independent of clonal selection, functional avidity maturation, and the integrity of proximal TCR signaling, but rather involves epigenetic modification of these cytokine genes. Activated Ag-specific CD8 T cells exhibit rapid DNA demethylation at the IL-2 and IFN-gamma loci and substantial histone acetylation at the IFN-gamma promoter and enhancer regions. These epigenetic modifications occur early after infection at the effector stage and are maintained through memory development. However, activated unhelped CD8 T cells, which fail to develop into functional memory and are incapable of rapid cytokine production, exhibit increased DNA methylation at the IL-2 promoter and fail to acetylate histones at the IFN-gamma locus. Thus, CD4 T cell help influences epigenetic modification during CD8 T(M) differentiation and these epigenetic changes provide a molecular basis for the enhanced responsiveness and the maintenance of a "ready-to-respond" state in CD8 T(M).