NKG2D receptor signaling shapes T cell thymic education

Author:

Perez Cynthia1,Plaza-Rojas Lourdes2,Boucher Justin C2,Nagy Mate Z2,Kostenko Elena2,Prajapati Kushal1,Burke Brianna1,Reyes Michael Delos1,Austin Anna L2,Zhang Shubin13,Le Phong T13,Guevara-Patino José A12

Affiliation:

1. Department of Cancer Biology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States

2. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, FL 33612, United States

3. Department of Microbiology and Immunology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States

Abstract

Abstract The role of natural killer group 2D (NKG2D) in peripheral T cells as a costimulatory receptor is well established. However, its contribution to T cell thymic education and functional imprint is unknown. Here, we report significant changes in development, receptor signaling, transcriptional program, and function in T cells from mice lacking NKG2D signaling. In C57BL/6 (B6) and OT-I mice, we found that NKG2D deficiency results in Vβ chain usage changes and stagnation of the double-positive stage in thymic T cell development. We found that the expression of CD5 and CD45 in thymocytes from NKG2D deficient mice were reduced, indicating a direct influence of NKG2D on the strength of T cell receptor (TCR) signaling during the developmental stage of T cells. Depicting the functional consequences of NKG2D, peripheral OT-I NKG2D-deficient cells were unresponsive to ovalbumin peptide stimulation. Paradoxically, while αCD3/CD28 agonist antibodies led to phenotypic T cell activation, their ability to produce cytokines remained severely compromised. We found that OT-I NKG2D-deficient cells activate STAT5 in response to interleukin-15 but were unable to phosphorylate ERK or S6 upon TCR engagement, underpinning a defect in TCR signaling. Finally, we showed that NKG2D is expressed in mouse and human thymic T cells at the double-negative stage, suggesting an evolutionarily conserved function during T cell development. The data presented in this study indicate that NKG2D impacts thymic T cell development at a fundamental level by reducing the TCR threshold and affecting the functional imprint of the thymic progeny. In summary, understanding the impact of NKG2D on thymic T cell development and TCR signaling contributes to our knowledge of immune system regulation, immune dysregulation, and the design of immunotherapies.

Funder

VoLo Foundation

Publisher

Oxford University Press (OUP)

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