CD6 modulates thymocyte selection and peripheral T cell homeostasis

Abstract

Orta-Mascaró, Lozano, and collaborators provide the first analysis of CD6-deficient mice, showing that this molecule modulates T cell receptor signaling and the threshold for thymocyte and peripheral T cell subset selection.

Abstract

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/ALCAM (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 Ca ²⁺ 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 (CD4 ⁺T _EM and CD8 ⁺T _CM) 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.