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

Abstract

Mature peripheral double negative (DN) T cells expressing αβ TCR but lacking CD4/CD8 co-receptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated CD4 and CD8 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. Since 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. While 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 superantigen staphylococcal enterotoxin B (SEB) were comparable between WT and DKO mice. Choric exposure to SEB precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers and kidneys, along with production of anti-nuclear antibodies 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.

αβ and γδ T cell receptors: Similar but different

“…This shows that αβ T cells that recognize Ags apart from pMHC can be positively selected if Lck is not sequestrated by CD4 or CD8. Importantly the numbers of thymic and peripheral γδ T cells are unaffected in CD4 and CD8 double KO mice . The independence of γδ T cells from CD4 and CD8 might be reflected in the different architecture of the γδ TCR compared to the αβ TCR.…”

“…Importantly the numbers of thymic and peripheral 𝛾𝛿 T cells are unaffected in CD4 and CD8 double KO mice. 36 The independence of 𝛾𝛿 T cells from CD4 and CD8 might be reflected in the different architecture of the 𝛾𝛿 TCR compared to the 𝛼𝛽 TCR. It has been shown that the conserved TCR-𝛼 CP is important for the interaction of murine 𝛼𝛽 TCRs with CD8.…”

Expansion of Double-Negative T Cells in Patients before Liver Transplantation Correlates with Post-Transplant Infections

“…DNT cells could express perforin, granzyme B and FasL to suppress CD4 + , CD8 + T cells’, B cells’, dendritic cells’ and NK cells’ activity [ 22 ], thus protecting the allograft against rejection in organ transplantation [ 6 , 23 , 24 , 25 , 26 , 27 , 28 ]. Strategies using adoptive transfer of DNT cells also prevented the development of graft versus host disease (GVHD) and autoimmune diseases [ 29 , 30 , 31 ]. DNT cells are also an important T cell population in the liver and kidneys.…”

NKG2D Enhances Double-Negative T Cell Regulation of B Cells

“…Unlike many receptors that are internalized after continuous stimulation, the CD4 molecule present on the surface of CD4 + T cells do not disappear via internalization ( 11 ). A recent study reported that concomitant disruption of the CD4 and CD8 genes facilitated the development of DNT cells in the periphery ( 25 ). This study used transgenic mice expressing human HLA class II molecules, HLA-DR3 or HLA-DQ8, as test subjects.…”