CD69+ resident memory T cells are associated with graft-versus-host disease in intestinal transplantation

Abstract

Graft-versus-host disease (GvHD) is a common, morbid complication after intestinal transplantation (ITx) with poorly understood pathophysiology. Resident memory T cells (T RM ) are a recently described CD69+ memory T cell subset localizing to peripheral tissue. We observed that T effector memory cells (T EM ) in the blood increase during GvHD and hypothesized that they derive from donor graft CD69+T RM migrating into host blood and tissue. To probe this hypothesis, graft and blood lymphocytes from 10 ITx patients with overt GvHD and 34 without were longitudinally analyzed using flow cytometry. As hypothesized, CD4+ and CD8+CD69+T RM were significantly increased in blood and grafts of GvHD patients, alongside higher cytokine and activation marker expression. The majority of CD69+T RM were donor derived as determined by multiplex immunostaining. Notably, CD8/PD-1 was significantly elevated in blood prior to transplantation in patients who later had GvHD, and percentages of HLA-DR, CD57, PD-1, and naïve T cells differed significantly between GvHD patients who died vs. those who survived. Overall, we demonstrate that (1) there were significant increases in T EM at the time of GvHD, possibly of donor derivation; (2) donor T RM in the graft are a possible source; and (3) potential biomarkers for the development and prognosis of GvHD exist.

Expansion kinetics of graft-versus-host T cell clones in patients with post-liver transplant graft-versus-host disease

“…Longitudinal analysis of donor T cell chimerism in recipient peripheral blood mononuclear cells (PBMCs) (Figure 1A, Figure S1) clearly revealed donor T cell macrochimerism (>4%) with a predominantly expressed effector memory phenotype in both CD4 and CD8 T cell (Figure 1B,C) in patients with GVHD (Pt62, Pt143) as reported in intestinal transplantation associated GVHD study, 4 whereas the non‐GVHD patients did not show donor T cell macrochimerism, which agrees with a previous report 5 …”

“…Longitudinal analysis of donor T cell chimerism in recipient peripheral blood mononuclear cells (PBMCs) (Figure 1A, Figure S1) clearly revealed donor T cell macrochimerism (>4%) with a predominantly expressed effector memory phenotype in both CD4 and CD8 T cell (Figure 1B,C) in patients with GVHD (Pt62, Pt143) as reported in intestinal transplantation associated GVHD study, 4 whereas the non-GVHD patients did not show donor T cell macrochimerism, which agrees with a previous report. 5 Pt143 showed significant donor T cell macrochimerism at postoperation day (POD) 31 prior to GVHD diagnosis (POD32), it maintained at a peak level during the disease progression (POD32-36), declined rapidly during the recovery period, and disappeared when the disease resolved (at POD55) (Figure 1A).…”

“…GVH T RM clones were also identified in pre‐LT liver‐graft. However, unlike in intestinal transplantation, 4,8 they were not dominant in recipient blood circulation, reflecting the compromised circulating ability of these hepatic GVH T RM even after activation in the recipient during GVHD.…”

The Microbiome and Metabolomic Profile of the Transplanted Intestine with Long-Term Function

“…Patients underwent routine loop ileostomy creation at the time of transplant for post-transplant monitoring, with planned restoration of intestinal continuity and closure of the ileostomy three to six months later. Post-transplant monitoring included endoscopy and biopsy twice weekly for the first 6 weeks, weekly until month three, biweekly until month six, and monthly thereafter, as previously described [ 14 , 15 ].…”

Graft Versus Host Disease After Intestinal Transplantation: A Single-center Experience

“…Recently, we have demonstrated that donor-derived clones in native colon mucosa of selected ITx recipients with typical features of GVHD have a CD69 + resident memory T-cell phenotype. 17 Complimentary to this work, we herein report our clinical GVHD experience after ITx with a heightened focus on risks for occurrence compared with ITx recipients not developing GVHD.…”