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Background    Foxn1 Δ/Δ   mutant mice have a specific defect in thymic development, characterized by a block in TEC differentiation at an intermediate progenitor stage, and blocks in thymocyte development at both the DN1 and DP cell stages, resulting in the production of abnormally functioning T cells that develop from an atypical progenitor population. In the current study, we tested the effects of these defects on thymic selection.    Methodology/Principal Findings  We used  Foxn1 Δ/Δ  ; DO11 Tg and  Foxn1 Δ/Δ  ; OT1 Tg mice as positive selection and  Foxn1 Δ/Δ  ; MHCII I-E mice as negative selection models. We also used an  in vivo  system of antigen-specific reactivity to test the function of peripheral T cells. Our data show that the capacity for positive and negative selection of both CD4 and CD8 SP thymocytes was reduced in  Foxn1 Δ/Δ   mutants compared to  Foxn1 +/Δ   control mice. These defects were associated with reduction of both MHC Class I and Class II expression, although the resulting peripheral T cells have a broad TCR Vβ repertoire. In this deficient thymic environment, immature CD4 and CD8 SP thymocytes emigrate from the thymus into the periphery. These T cells had an incompletely activated profile under stimulation of the TCR signal  in vitro , and were either hypersensitive or hyporesponsive to antigen-specific stimulation  in vivo . These cell-autonomous defects were compounded by the hypocellular peripheral environment caused by low thymic output.    Conclusions/Significance  These data show that a primary defect in the thymic microenvironment can cause both direct defects in selection which can in turn cause indirect effects on the periphery, exacerbating functional defects in T cells.

Impaired Thymic Selection and Abnormal Antigen-Specific T Cell Responses in Foxn1Δ/Δ Mutant Mice