A novel role for CD28 in thymic selection: elimination of CD28/B7 interactions increases positive selection

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Abstract
While the importance of the CD28/B7 costimulation pathway is well established for mature T cells, the role of CD28 in thymocyte selection is less well defined. The role of CD28 in both negative and positive selection was assessed using H‐Y‐specific TCR‐transgenic (Tg) RAG‐2‐deficient (H‐Yrag) mice. Negative selection in male H‐Yrag mice was not affected by deficiency in CD28 or B7. Surprisingly, absence of CD28 or B7 in H‐Yrag females resulted in increased numbers of CD8 single‐positive (SP) thymocytes. The CD8 SP thymocytes found in these females were mature and functionally competent. Furthermore, double‐positive (DP) thymocytes from CD28‐knockout (CD28KO) or B7.1/B7.2 double‐KO (B7DKO) females had higher levels of both CD5 and TCR than those from WT females, consistent with a stronger selecting signal. CD28KO H‐Yrag fetal thymic organ cultures also had elevated numbers of thymic CD8 SP cells, reflecting increased thymic differentiation and not recirculation of peripheral T cells. Finally, increased selection of mature CD4 and CD8 SP T cells was observed in non‐TCR‐Tg CD28KO and B7DKO mice, indicating that this function of CD28‐B7 interaction is not unique to a TCR‐Tg model. Together these findings demonstrate a novel negative regulatory role for CD28 in inhibiting differentiation of SP thymocytes, probably through inhibition of thymic selection.