Concomitant Disruption of CD4 and CD8 Genes Facilitates the Development of Double Negative αβ TCR + Peripheral T Cells That Respond Robustly to Staphylococcal Superantigen

• Published in: The Journal of immunology (1950) 2017-06, Vol.198 (11), p.4413-4424
• Main Authors: Chowdhary, Vaidehi R, Krogman, Ashton, Tilahun, Ashenafi Y, Alexander, Mariam P, David, Chella S, Rajagopalan, Govindarajan
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune diseases; Bacteria; CD3 antigen; CD4 antigen; CD4 Antigens - genetics; CD4 Antigens - immunology; CD8 antigen; CD8 Antigens - genetics; CD8 Antigens - immunology; Cell activation; Chronic exposure; Clonal selection; Enterotoxins - immunology; Foxp3 protein; Histocompatibility antigen HLA; Histocompatibility Antigens Class II - immunology; HLA-DQ Antigens - genetics; HLA-DQ Antigens - immunology; HLA-DR3 Antigen - genetics; HLA-DR3 Antigen - immunology; Immunoregulation; Kidneys; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mice; Mice, Knockout; Mice, Transgenic; Monocytes; Positive selection; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Rodents; Spleen; Spleen - cytology; Spleen - immunology; Staphylococcal enterotoxin A; Staphylococcal enterotoxin B; Superantigens; Superantigens - immunology; T cell receptors; T-Lymphocyte Subsets - immunology; Thymocytes; Thymus; Thymus Gland - cytology; Thymus Gland - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601991

Mature peripheral double negative T (DNT) cells expressing αβ TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated and genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3 αβ TCR thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3 αβ TCR cells and Foxp3 T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.