Anti-ITGAE monoclonal antibody, clone PY-73 [R-PE]

Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8(+) T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103(+)CD8(+) T cell response to acute viral infection remain unclear. Although TGF beta signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGF beta-SKI-Smad4 pathway that critically and specifically directs resident CD103(+)CD8(+) T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103(+)CD8(+) T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8(+) T cell response to acute viral infection. There is a reduction in resident CD103(+)CD8(+) T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8(+) T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103(+)CD8(+) T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103(+)CD8(+) T cell response to promote protective immunity.

V delta 2V gamma 9 T cells are the dominant gamma delta T-cell subset in human peripheral blood. V delta 2 T cells recognize pyrophosphate molecules derived from microbes or tumor cells; hence, they play a role in antimicrobial and antitumor immunity. TGF-beta, together with IL-15, induces a regulatory phenotype in V delta 2 T cells, characterized by forkhead box protein P3 (FoxP3) expression and suppressive activity on CD4 T-cell activation. We performed a genome-wide transcriptome analysis and found that the same conditions (TGF-beta plus IL-15) strongly enhanced the expression of additional genes in V delta 2 T cells, including IKAROS family zinc finger 4 (IKZF4; Eos), integrin subunit alpha E (ITGAE; CD103/ alpha E beta 7), and IL9. This up-regulation was associated with potent IL-9 production as revealed by flow cytometry and multiplex analysis of cell culture supernatants. In contrast to CD4 and CD8 alpha beta T cells, gamma delta T cells did not require IL-4 for induction of intracellular IL-9 expression. Upon antigen restimulation of V delta 2 T cells expanded in vitro in the presence of TGF-beta and IL-15, IL-9 was the most abundant among 16 analyzed cytokines and chemokines. IL-9 is a pleiotropic cytokine involved in various (patho) physiological conditions, including allergy and tumor defense, where it can promote antitumor immunity. Given the conspicuous sensitivity of many different tumors to V delta 2 T-cell-mediated killing, the conditions defined here for strong induction of IL-9 might be relevant for the development of V delta 2 T-cell-based immunotherapy.