Reduced MCMV Δm157 viral clearance in the absence of TSAd

Abstract

The T cell specific adapter protein (TSAd) is expressed in activated T cells and NK cells. While TSAd is beginning to emerge as a critical regulator of Lck and Itk activity in T cells, its role in NK cells has not yet been explored. Here we have examined susceptibility to virus infections in a murine model using various viral infection models. We report that TSAd-deficient mice display reduced clearance of murine cytomegalovirus (MCMV) that lack the viral MHC class I homologue m157, which is critical for Ly49H-mediated NK cell recognition of infected cells. In this infection model, NK cells contribute in the early stages of the disease, whereas CD8+ T cells are critical for viral clearance. We found that mice infected with MCMV Δm157 displayed reduced viral clearance in the spleen as well as reduced proliferation in spleen NK cells and CD8+ T cells in the absence of TSAd. Though no other immunophenotype was detected in the infection models tested, these data suggests that in the absence of the Ly49H ligand activation, NK cell and CD8+ T cell responses may be compromised in TSAd-deficient mice.

Adaptor proteins: Flexible and dynamic modulators of immune cell signalling

“…Additionally, protein kinase A (cAMP‐dependent protein kinase) activity is required for TCR‐dependent induction of TSAd expression 180 . Another potent activator of TSAd expression is a combination of phorbol myristate acetate and ionomycin (which bypasses immunoreceptor tyrosine‐based activation motif phosphorylation), both in T cells and NK cells 181 …”

“…Additionally, TSAd KO mice are more resistant to myeloma development than TSAd wild‐type mice in a myeloma‐specific TCR‐transgenic model 186 . Upon viral challenge, TSAd‐deficient mice displayed reduced clearance of murine cytomegalovirus in the spleen 181 . Murine SH2D2A −/− CD4 + T cells exhibited impaired polarization in the immunological synapse of multiple molecules involved in TCR signalling 190 .…”

“…186 Upon viral challenge, TSAd-deficient mice displayed reduced clearance of murine cytomegalovirus in the spleen. 181 Murine SH2D2A −/− CD4 + T cells exhibited impaired polarization in the immunological synapse of multiple molecules involved in TCR signalling. 190 Moreover, TSAd KO mice displayed accelerated rejection of heart transplants in an MHC class II-mismatched model, and resistance to graft-prolonging therapy of costimulatory blockade in the fully mismatched model.…”

Polarity of CD4+ T cells towards the antigen presenting cell is regulated by the Lck adapter TSAd

“…Despite TSAd being involved in TCR signalling, unchallenged Sh2d2a −/− mice display only minor alteration in overall immune phenotype 15 , 19 , 20 . TSAd may influence specific NK cell immune responses, since Sh2d2a −/− mice displayed reduced clearance of a mutant murine cytomegalovirus which does not activate the NK cell receptor Ly49H 21 . Recently, we found that TSAd affects CD4+ T cell-mediated rejection of experimental multiple myeloma 19 .…”

Interaction of T‐cell‐specific adapter protein with Src‐ and Tec‐family kinases

“…TSAd is rapidly induced at the mRNA and protein levels upon activation of T cells. [3][4][5][6] In addition, TSAd is expressed in natural killer (NK) cells 7,8 and in various epithelial cells. [9][10][11][12][13][14] Mice lacking TSAd display normal T cell differentiation, while the T cell receptor-induced proliferation of murine T cells is attenuated.…”