Predominant donor CD103+CD8+ T cell infiltration into the gut epithelium during acute GvHD: a role of gut lymph nodes

Abstract

The existence of donor effector cell subsets responsible for either gut or skin graft-versus-host disease (GvHD) is still undetermined. We examined the trafficking and role of donor CD8(+) intra-epithelial lymphocytes (IELs) in the gut and skin epithelia concerning alpha E beta 7 integrin (CD103) expression, using a rat acute lethal GvHD model. Most CD103(+) donor cells were CD8(+) and showed a proliferative activity in the target epithelia. On the other hand, activated donor T cells in the host lymphoid tissues did not express CD103, indicating the presence of CD8(+) IEL precursors in the lymphoid tissues that may up-regulate CD103 only after migrating to the target organs. At the late stage of GvHD, while >80% of the donor CD8(+) IELs were CD103(+) in the gut epithelium, both CD4(+) and CD103(+)CD8(+) T cells evenly accumulated in the skin epidermis. The CD103 expression by donor CD8(+) IELs especially in the gut was also correlated with the clinical GvHD manifestations. Furthermore, the selective removal of gut lymph nodes (LNs) but not skin LNs suppressed the infiltration of CD103(+) donor IELs in the gut and alleviated intestinal GvHD. In conclusion, CD103(+)CD8(+) donor T cells predominantly infiltrate into the gut epithelium and are responsible for the manifestations of intestinal GvHD. This pathology is at least partly dependent on the gut LNs.

Integrin αEβ7: Molecular Features and Functional Significance in the Immune System

“…This view is further supported by the observation that T cells from aE null/null mice do not elicit gut graft-versus-host disease (GVHD) on transfer to wildtype allogenic recipients [24]. Zhou et al [118] confirmed these findings in a rat GVHD model, and further observed that the skin epidermis in rats during GVHD is infiltrated by an equal number of CD4 + T cells and CD8 + T cells expressing aEb7. Collazo et al [19] reported that expression of SH2 domain-containing inositol 5-phosphatase (SHIP) is required for robust expansion of donor aEb7 + CD4 + T cells during graft-versus-host and host-versusgraft responses by CD4 + T cell and limits their immunoregulatory capacity.…”

Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting CC-chemokine receptor 7 on donor T cells

“…For example, recipient Peyer patches (PPs) and mesenteric lymph nodes (MLNs) may be important for the induction of gastrointestinal GVHD. 4,5 Other studies, however, have suggested a more significant redundancy among the various recipient lymphoid tissues, without a direct link between a given lymphatic organ and a specific GVHD manifestation. Notably, irradiated B6 lymphotoxin-␣ receptordeficient mice, which lack PPs and MLNs but possess an intact spleen, appear to develop intestinal acute GVHD that is similar to that of wild-type (WT) B6 recipients when given transplants across a complete major histocompatibility complex (MHC) mismatch.…”

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

“…CD8 + /a E b 7 + T lymphocytes have been reported to play a critical role in mediating tubular injury following allogeneic renal transplantation (5) and in promoting renal allograft rejection (6,7). They are also involved in selective destruction of pancreatic islet allografts (8) and host intestinal epithelium during graftversus-host disease (9)(10)(11)(12), which can be prevented by CD103 deficiency (13). The a E b 7 integrin is expressed at high levels by mucosal CD8 + T lymphocytes, in particular intestinal epithelium lymphocytes (14), psoriatic skin epidermal CD8 + T cells (15), and cervicovaginal Ag-specific CTL (16).…”