CD6 modulates thymocyte selection and peripheral T cell homeostasis

Orta-Mascaró et al.The CD6 glycoprotein is a lymphocyte surface receptor putatively involved in T cell development and activation. CD6 facilitates adhesion between T cells and antigen-presenting cells through its interaction with CD166/ALC AM (activated leukocyte cell adhesion molecule), and physically associates with the T cell receptor (TCR) at the center of the immunological synapse. However, its precise role during thymocyte development and peripheral T cell immune responses remains to be defined. Here, we analyze the in vivo consequences of CD6 deficiency. CD6-/- thymi showed a reduction in both CD4 and CD8 single-positive subsets, and double-positive thymocytes exhibited increased Ca2 mobilization to TCR cross-linking in vitro. Bone marrow chimera experiments revealed a T cell-autonomous selective disadvantage of CD6-/- T cells during development. The analysis of TCR-transgenic mice (OT-I and Marilyn) confirmed that abnormal T cell selection events occur in the absence of CD6. CD6-/- mice displayed increased frequencies of antigen-experienced peripheral T cells generated under certain levels of TCR signal strength or co-stimulation, such as effector/memory (CD4TEM and CD8TCM) and regulatory (T reg) T cells. The suppressive activity of CD6-/- T reg cells was diminished, and CD6-/- mice presented an exacerbated autoimmune response to collagen. Collectively, these data indicate that CD6 modulates the threshold for thymocyte selection and the generation and/or function of several peripheral T cell subpopulations, including T reg cells.This work is supported by grants from: Worldwide Cancer Research (14-1275) and Fundació La Marató TV3 (201319-30) to F. Lozano; Spanish Ministerio de Economía y Competitividad (Plan Nacional I+D+i) co-financed by European Development Regional Fund “A way to achieve Europe” to F. Lozano (SAF2013-46151-R), J. Merino (SAF2012-34059), R. Merino (SAF2014-55088-R), and R. Vicente (SAF2014- 52228-R); IPT2011-1527-010000 (associated to Fibrostatin SL) to J. Merino; and Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, European Research Council (FP7/2007–2013 grant no. 322465), and ANR grant Basilic to B. Malissen and M. Malissen. M. Orta-Mascaró, I. Simões, and E. Carreras are recipients of fellowships from Ministerio de Economía y Competitividad (BES-2011-048415), Fundação para a Ciência e a Tecnologia (SFRH/ BD/75738/2011), and European Community Seventh Framework Program (BIOTRACK, FP7/2007/2013;229673), respectively. National Institutes of Health grants to Velocigene at Regeneron Inc. (U01HG004085), and the CSD Consortium (U01HG004080) funded the generation of gene-targeted vectors and ES cells for 8,500 genes in the KOMP Program and archived and distributed by the KOMP Repository at UC Davis and CHORI (U42RR024244).Peer Reviewe