Discriminating the contributions of CCR4 and CCR7 to thymic central tolerance

University Of Texas At Austin, Austin TX

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Abstract

ABSTRACT As T cells develop in the thymus, VDJ recombination generates diverse T cell receptors (TCRs) needed to recognize the myriad pathogens encountered throughout life, but also yields TCRs that recognize self-antigens and could thus induce autoimmunity. Central tolerance limits autoimmunity by enforcing negative selection of thymocytes expressing TCRs with high affinity for self-antigens or diverting them to the regulatory T cell (Treg) lineage. To undergo self-tolerance, thymocytes must enter the thymic medulla, where they encounter dendritic cells (DCs) and medullary thymic epithelial cells (mTECs), key antigen presenting cell types that collectively display most self-antigens. Recent data suggest that thymic DCs express proteins induced during inflammation, while mTECs display tissue-restricted self-antigens (TRAs) expressed at steady state by differentiated cell types. Establishing T-cell tolerance to inflammation associated self-antigens, such as cytokines, is critical for mounting productive immune responses to pathogens, while establishing tolerance to TRAs is essential for preventing tissue-specific autoimmunity. Our findings over the previous project period demonstrate that the chemokine receptors CCR4 and CCR7 cooperate to promote thymocyte medullary entry and negative selection, but also suggest a new model in which CCR4 promotes early-stage tolerance to inflammation-associated self-antigens expressed by DCs, while CCR7 promotes late-stage tolerance to TRAs expressed by mTECs. We recently found that CCR4 and CCR7 are sequentially expressed by and promote medullary entry and negative selection of immature versus mature post-positive selection thymocyte subsets, respectively. In keeping with a cooperative role in supporting thymocyte medullary entry, double deficiency in CCR4 and CCR7 more severely impairs negative selection. However, distinct roles for these receptors in regulating central tolerance is suggested by the finding that CCR4 and CCR7 ligands are expressed by activated thymic DCs versus mTECs, respectively. Also, CCR4 deficiency enhances autoreactive T-cell responses to activated DCs, while CCR7 deficiency yields lymphocytic infiltrates in differentiated tissues. These findings support a new model in which CCR4 and CCR7 promote central tolerance to inflammation-associated antigens expressed by DCs and TRAs expressed by mTECs, respectively (Aims 1-2). Also, CCR4 is expressed by recirculating Treg, which suppress new Treg selection, while CCR7 is expressed by and supports survival of thymic DCs that present TRAs. Thus, CCR4 and CCR7 may promote central tolerance not only by impacting location and cellular interactions of thymocytes, but also by altering the activity of recirculating thymic Treg and DCs (Aims 1-2). Finally, autoimmunity in CCR4 and CCR7 deficient mice may reflect failed central and/or peripheral tolerance mechanisms of T cells and/or Treg (Aim 3). Altogether, the proposed experiments will test key tenets and mechanisms of the model that CCR4 and CCR7 respectively enforce thymic tolerance to inflammatory versus tissue-restricted self-antigens.