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Post-thymic maturation influences CD4+ recent thymic emigrant lineage commitment and function
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Post-thymic maturation influences CD4+ recent thymic emigrant lineage commitment and function
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Post-thymic maturation influences CD4+ recent thymic emigrant lineage commitment and function
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Dissertation
Post-thymic maturation influences CD4+ recent thymic emigrant lineage commitment and function
2010
Overview
Recent thymic emigrants (RTEs) are the youngest T cells in the periphery, having recently completed the complex process of intra-thymic development. RTEs are an important source of new TCR specificities throughout life, and they help reconstitute the peripheral T cell pool in neonates and those suffering from lymphopenic conditions. RTEs exit the thymus in an immature state, undergoing both phenotypic and functional maturation during the first 3 weeks they reside in the periphery. CD4+ RTEs exhibit defects in proliferation, IL-2 production and CD25 upregulation compared to their more mature, but still naïve (MN), peripheral T cell counterparts. The capacity for CD4 + RTEs to differentiate into the various T helper (Th) lineages and generate a mature Th effector response is still poorly understood. Using a well-controlled in vitro polarization scheme, we show here that CD4+ RTEs are defective in Th0, Th1, Th17 and regulatory T cell lineage commitment, with dampened cytokine production and transcription factor expression. In contrast, in a Th2 environment, CD4+ RTES are biased toward this lineage both in vitro and in vivo, with more robust IL-4, IL-5 and IL-13 production than their MN T cell counterparts. Co-culture experiments demonstrate that MN T cells influence neighboring RTEs in their Th responses In adoptive hosts, CD4 + RTEs drive production of the Th2-associated antibody isotype IgG1 and mediate airway inflammatory disease. Despite diminished Th1 effector function in vitro, CD4+ RTEs can overcome their functional defects under certain conditions in vivo. The distinct Th effector function exhibited by RTEs likely results from dampened negative regulation of the Th2 lineage by diminished levels of T-bet, a key Th1 transcription factor. CD4+ RTEs exhibit a unique signaling \"signature\" with differential gene expression and epigenetic regulation compared to MN T cells. CD4+ RTEs thus represent a peripheral T cell population with a distinct interpretation of, and response to, immunological cues. These characteristics may be beneficial during the post-thymic maturation period to avoid inappropriate immune responses, particularly in lymphopenic neonates and adults.
