Neonatal and adult T cells differ in their effector functions. Although it is known that cell-intrinsic differences in mature T cells contribute to this phenomenon, the factors involved remain unclear. Given emerging evidence that the binding strength of a TCR for self-peptide presented by MHC (self-pMHC) impacts T cell function, we sought to determine whether altered thymic selection influences the self-reactivity of the TCR repertoire during ontogeny. We found that conventional and regulatory T cell subsets in the thymus of neonates and young mice expressed higher levels of cell surface CD5, a surrogate marker for TCR avidity for self-pMHC, as compared with their adult counterparts, and this difference in self-reactivity was independent of the germline bias of the neonatal TCR repertoire. The increased binding strength of the TCR repertoire for self-pMHC in neonates was not solely due to reported defects in clonal deletion. Rather, our data suggest that thymic selection is altered in young mice such that thymocytes bearing TCRs with low affinity for self-peptide are not efficiently selected into the neonatal repertoire, and stronger TCR signals accompany both conventional and regulatory T cell selection. Importantly, the distinct levels of T cell self-reactivity reflect physiologically relevant differences based on the preferential expansion of T cells from young mice to fill a lymphopenic environment. Therefore, differences in thymic selection in young versus adult mice skew the TCR repertoire, and the relatively higher self-reactivity of the T cell pool may contribute to the distinct immune responses observed in neonates.

Highlights d Differences among naive CD4 + T cells are driven by TCR genes and chromatin modifiers d Pre-existing gene expression differences are maintained post-activation d CD5 hi naive CD4 + T cells have a greater propensity to become T FH cells d Distinct chromatin accessibility landscapes are established during thymic development

The Coiled Coil Domain Containing Protein 88B (CCDC88B) gene is associated with susceptibility to several inflammatory diseases in humans and its inactivation in mice protects against acute neuroinflammation and models of intestinal colitis. We report that mice lacking functional CCDC88B (Ccdc88b Mut) are defective in several dendritic cells (DCs)-dependent inflammatory and immune reactions in vivo. In these mice, an inflammatory stimulus (LPS) fails to induce the recruitment of DCs into the draining lymph nodes (LNs). In addition, OVA-pulsed Ccdc88b Mut DCs injected in the footpad do not induce recruitment and activation of antigen-specific CD4 + and CD8 + T cells in their draining LN. Experiments in vitro indicate that this defect is independent of the ability of mutant DCs to capture and present peptide antigen to T cells. Rather, kinetic analyses in vivo of wild-type and Ccdc88b Mut DCs indicate a reduced migration capacity in the absence of the CCDC88B protein expression. Moreover, using time-lapse light microscopy imaging, we show that Ccdc88b Mut DCs have an intrinsic motility defect. Furthermore, in vivo studies reveal that these reduced migratory properties lead to dampened contact hypersensitivity reactions in Ccdc88b mutant mice. These findings establish a critical role of CCDC88B in regulating movement and migration of DCs. Thus, regulatory variants impacting Ccdc88b expression in myeloid cells may cause variable degrees of DC-dependent inflammatory response in situ, providing a rationale for the genetic association of CCDC88B with several inflammatory and autoimmune diseases in humans.

No abstract

T-cell division is central to maintaining a stable T-cell pool in adults. It also enables T-cell expansion in neonates, and after depletion by chemotherapy, bone marrow transplantation, or infection. The same signals required for T-cell survival in lymphoreplete settings, IL-7 and T-cell receptor (TCR) interactions with self-peptide MHC (pMHC), induce division when T-cell numbers are low. The strength of reactivity for self-pMHC has been shown to correlate with the capacity of T cells to undergo lymphopenia-induced proliferation (LIP),in that weakly self-reactive T cells are unable to divide, implying that T-cell reconstitution would significantly skew the TCR repertoire toward TCRs with greater self-reactivity and thus compromise T-cell diversity. Here, we show that while CD4 + T cells with low self-pMHC reactivity experience more intense competition, they are able to divide when present at low enough cell numbers. Thus, at physiological precursor frequencies CD4 + T cells with low self-pMHC reactivity are able to contribute to the reconstitution of the T-cell pool.Keywords: Lymphopenia-induced proliferation r Regulation of homeostasis r T-cell competition r T-cell diversity r T-cell repertoire Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe size of the naïve T-cell pool is tightly regulated. On average, naïve T cells are long-lived, but both in humans and mice there is continual turnover with cells dying and being replaced. Two sources of renewal contribute to naïve T-cell maintenance: de novo production in the thymus and proliferation within secondary Correspondence: Dr. Nienke Vrisekoop and Dr. Judith Mandl e-mail: n.vrisekoop@umcutrecht.nl; judith.mandl@mcgill.ca lymphoid organs. In adults, when thymic production diminishes, 90% of daily naïve T-cell production derives from proliferation [1]. Moreover, restoration of naïve T-cell numbers after acute T-cell depletion, whether caused by infection, chemotherapy, or bone marrow transplantation requires cell division. Both naïve T-cell division and cell survival are dependent on extrinsic cues provided by IL-7 and tonic trophic signals obtained via the T-cell receptor (TCR) through interaction with specific self-pMHC [2][3][4][5][6][7].It is well-established that T-cell division during antigen-specific responses is a function of the number of the antigen-specific T cells present, such that large numbers of T cells with the same TCR inhibits their expansion [8,9]. There is also evidence that T cells compete for the sub-threshold self-pMHC signals critical to T-cell maintenance. In lympho-replete mice, T cells have a longer average life span when there are less competitor cells present with the same TCR [10]. Furthermore, during lymphopenia-induced proliferation (LIP), T cells divide in the presence of T cells with a distinct TCR, but not when there are large numbers of T cells present with the same TCR [11][12][13]. This suggests that signals obtained from sub-threshold interactions...