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)

Subject

Cell Biology,Immunology,Immunology and Allergy

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