Abstract
Recent thymic emigrants (RTEs) represent a source of antigen-naïve T cells that enter the periphery throughout life. However, whether RTEs contribute to the control of chronic parasitic infection and how their potential might be harnessed by therapeutic intervention is currently unclear. Here, we show that CD4+ recent thymic emigrants emerging into the periphery of mice with ongoing Leishmania donovani infection undergo partial activation and are recruited to sites of granulomatous inflammation. However, CD4+ RTEs displayed severely restricted differentiation either into IFNγ+ or IFNγ+TNFα+ effectors, or into IL-10-producing regulatory T cells. Effector cell differentiation in the chronically infected host was not promoted by adoptive transfer of activated dendritic cells or by allowing extended periods of post-thymic differentiation in the periphery. Nevertheless, CD4+ RTEs from infected mice retained the capacity to transfer protection into lymphopenic RAG2-/- mice. Taken together, our data indicate that RTEs emerging into a chronically inflamed environment are not recruited into the effector pool, but retain the capacity for subsequent differentiation into host protective T cells when placed in a disease-free environment.
Highlights
Visceral leishmaniasis (VL) is a systemic disease caused by the intracellular parasites Leishmania donovani and L. infantum, and can be fatal if left untreated
In order to study the functional differentiation of Recent thymic emigrants (RTEs) that emerge into the periphery during chronic infection, we used the myeloablative drug busulfan [38] to create bone marrow microchimeras in which genetically identifiable RTEs emerge after the onset of disease-associated immunopathology (Fig 1)
RTEs already in the periphery may contribute to the primary immune response to infection, the fate of recent thymic emigrants that emerge from the thymus into this complex environment has not been previously studied, but has important implications for the design of therapeutic strategies to enhance host protective immunity during chronic infection
Summary
Visceral leishmaniasis (VL) is a systemic disease caused by the intracellular parasites Leishmania donovani and L. infantum, and can be fatal if left untreated. Experimental VL (EVL) in C57BL/6 mice is typified by organ-specific immune responses that result in a self-limiting disease in the liver and a chronic persisting infection with extensive immunopathology in the spleen. Associated with chronic infection of the spleen is a dramatic remodelling of stromal. Recent Thymic Emigrants in L. donovani Infection collection and analysis, decision to publish, or preparation of the manuscript
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