Smad and NFAT Pathways Cooperate To Induce CD103 Expression in Human CD8 T Lymphocytes

Abstract

The interaction of integrin αE(CD103)β7, often expressed on tumor-infiltrating T lymphocytes, with its cognate ligand, the epithelial cell marker E-cadherin on tumor cells, plays a major role in antitumor CTL responses. CD103 is induced on CD8 T cells upon TCR engagement and exposure to TGF-β1, abundant within the tumor microenvironment. However, the transcriptional mechanisms underlying the cooperative role of these two signaling pathways in inducing CD103 expression in CD8 T lymphocytes remain unknown. Using a human CTL system model based on a CD8+/CD103− T cell clone specific of a lung tumor–associated Ag, we demonstrated that the transcription factors Smad2/3 and NFAT-1 are two critical regulators of this process. We also identified promoter and enhancer elements of the human ITGAE gene, encoding CD103, involved in its induction by these transcriptional regulators. Overall, our results explain how TGF-β1 can participate in CD103 expression on locally TCR-engaged Ag-specific CD8 T cells, thus contributing to antitumor CTL responses and cancer cell destruction.

CD8+CD103+ Tumor–Infiltrating Lymphocytes Are Tumor-Specific Tissue-Resident Memory T Cells and a Prognostic Factor for Survival in Lung Cancer Patients

“…The essential cause of this variation is not clearly understood, but it may reflect interpatient variations in the intratumoral level of TGF-b1 or factors involved in its activation, such as a V integrins (30,31), the number of tumor Ag-specific T cell precursors, or both. Indeed, as mentioned above, engagement of both the TGF-b1 receptor and TCR via an active form of TGF-b1 and the tumor peptide/MHC-I complex, respectively, is required for CD103 induction (11). Thus, TGF-b1, considered as an immunosuppressive cytokine, can control immune responses to viral infections and tumors via induction of CD103 and formation of CD8 + CD103 + T RM T cells.…”

“…It has been recently reported that CD103 expression on TIL is associated with increased survival in high-grade serous ovarian cancer (10). This integrin is induced on CD8 + T lymphocytes upon TCR engagement and exposure to TGF-b1, abundant within the tumor microenvironment, through binding of NFAT-1 and Smad2/3 transcription factors to the promoter and enhancer elements of the ITGAE gene that encodes CD103 (11).…”

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

“…One signal reported to play a role is transforming growth factor (TGF)‐β1. TGF‐β1 induces CD103 expression through nuclear factor of activated T cells (NFAT)‐1 and suppressor of mothers against decapentaplegic (Smad)2/3 transcription factors binding to the promoter region of the ITGAE gene, encoding for CD103 [5]. Correspondingly, a similar effect has been demonstrated in TGF‐β‐rich tumours, in which T RM cells are consequently generated [6].…”

The Transcription Factor Ehf Is Involved in TGF-β–Induced Suppression of FcεRI and c-Kit Expression and FcεRI-Mediated Activation in Mast Cells

“…1C). Mokrani et al (20) reported that CD103 expression is induced by signaling through Smad and NFAT pathways in human CD8 T cells. However, the mechanism by which TGF-b1 suppresses the expression of FcεRI and c-Kit on the mast cell surface is unknown.…”

“…TGF-b signaling is mediated by Smads, which accumulate in the nucleus to transcriptionally regulate TGF-b target genes. The promoter and enhancer element of Itgae, encoding CD103, are known to have Smad-binding elements (20). Thus, CD103 expression is directly regulated by TGF-b/Smad signaling.…”