Natural Killer Group 2D (NKG2D) Receptor Signaling Shapes T Cell Thymic Education and Their Functional Imprint

Abstract

Few costimulatory molecules have been shown to deeply impact the development and function of CD8 T cells. To our knowledge, only CD28, the archetype of TCR co-stimulation, has been reported to affect thymic T cell development. The role of NKG2D in peripheral T cells as a TCR costimulatory receptor is well established. However, its contribution to thymic education is unknown. We present data indicating noticeable differences in T cell development, TCR signaling, function and transcriptional program of T cells from NKG2D deficient mice compared to WT mice. We found changes in the Vβ chain usage and stagnation of the double-positive (DP) stage. Mechanistically, these changes were accompanied by TCR signaling strength reduction, shown by TCR Vβ5 chain, CD3, CD5 and CD45 reductions. Functionally, we found that peripheral T cells were unresponsive to peptide stimulation. Conversely, aCD3/CD28 antibodies mediated their phenotypic activation; however, generated functionally impotent cells. Finally, underpinning a defect in TCR signaling, we found that NKG2D deficient cells were unable to phosphorylate ERK or S6. From these data, we concluded that NKG2D shapes T cell thymic education and their functional imprint.