TGF-β–dependent CD103 expression by CD8+ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease

Abstract

Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8+ T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8+ T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-β dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-β activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8+ T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-β–dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8+ T cells during GVHD pathogenesis.

Induction of Graft-versus-host Disease and <em>In Vivo</em> T Cell Monitoring Using an MHC-matched Murine Model

“…Pseudo-colored scale shows varying light emittance throughout the body with the highest light intensity being emitted in the spleen and the gut. CD8 T cell accumulation in the gut is consistent with previous findings 6 . Recipient mice can be placed back in microisolator cage to be imaged at a later time point or euthanized for ex vivo imaging.…”

“…Combine 10 7 CD3 depleted bone marrow cells, 18x10 6 WT (CD8 depleted) splenocytes, and 2x10 6 L2G85.B6 purified CD8 T cells in a microcentrifuge tube. Wash with sterile PBS and resuspend in 300 μl.…”

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

“…Interestingly, the classical Treg markers CD73 and CD103 were selectively expressed by induced CD8 1 Foxp3 1 T cells, underlining that their expression is dependent on TGF-b, RA and/or Foxp3. In line with this, CD8 1 T cells deficient in TGF-b signaling fail to up-regulate CD103 in a GVHD model [39], and Foxp3 has been shown to directly bind the CD103 promoter [40]. However, Foxp3-independent mechanisms can also activate CD103 [3], consistent with the only mildly reduced induction of CD103 expression in stimulated T cells from DEREG Â Rag1 À/À Â OTI Â Sf mice (Supporting Information Fig.…”

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

“…Emerging evidence points to a role for CD8 + CD103 + T cells in transplant rejection and in protecting prevalent infections posttransplantation (14)(15)(16). This integrin serves as a marker of tissue-resident memory (T RM ) T cells, and accumulating evidence indicates that CD103 is directly involved in intraepithelial retention of T RM T cells (17).…”