Comparative analysis of FoxP3+ regulatory T cells in the target tissues and blood in chronic graft versus host disease

Abstract

Activation and migration of regulatory T cells (Treg) into tissue is critical in control of inflammation, but has not been examined extensively in chronic graft versus host disease (cGVHD). In parallel studies of tissues and blood, we determined that FoxP3(+) T cells increased in proportion to T effectors (Teff) in tissue infiltrates in oral and cutaneous lichenoid cGVHD. These FoxP3(+) cells expressed distinguishing phenotypic and functional markers of Treg (CD3(+), CD4(+), CD27(+), ICOS(+) and CD39(+)), not found on FoxP3(-) Teff. Both Teff and FoxP3(+) Treg expressed T-bet and the chemokine receptor CXCR3, however, consistent with a common mechanism of chemokine-mediated migration into tissue. Furthermore, functional markers (ICOS and CD39) and chemokine receptors (CXCR3) were both present in a higher proportion of FoxP3(+) cells in tissues than in peripheral blood, consistent with recruitment and activation of Treg in cGVHD target tissues. Finally, the 'activated' CD45RA(-)FoxP3(hi) subset of Treg cells, which highly express functional markers, were found in comparable frequencies in cGVHD patients and normal controls, despite a significant deficit in naive 'resting' Treg. These findings are consistent with Treg capacity to upregulate functional markers and traffick into tissue in cGVHD.

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

“…Previous studies explored the roles of Treg cells in cGVHD that were mainly obtained from the patient's sample after the diagnosis of cGVHD. 5,17,18 In this study, we prospectively accrued and serially evaluated a cohort of patients after allo-HSCT to evaluate the "natural history" of cGVHD after unmanipulated transplantation either with or without IL-2 treatment, which would provide direct evidence to further clarify the protective roles of Treg cells as well as the protective effect of IL-2 treatment on cGVHD.…”

Pulmonary sarcoidosis is associated with high-level inducible co-stimulator (ICOS) expression on lung regulatory T cells – possible implications for the ICOS/ICOS-ligand axis in disease course and resolution

“…Moreover, increased ICOS expression on lung T regs was evident only in the sarcoidosis patients and was not observed in healthy controls, underlining the fact that ICOS over-expressing T regs in the lung of sarcoidosis patients exhibit an 'inflammationseeking' phenotype. Accumulation of ICOS high T regs in the inflamed tissue might be due to the high probability of migrating ICOS 1 T regs that might express the chemokine receptor CXCR3 guiding them into the inflamed lungs [40]. Therefore, we may speculate that the chemoattraction of ICOS 1 T regs from the periphery to, or their induction/ expansion in, the inflamed lungs might represent a mechanism counteracting ongoing inflammation in the lung which is particularly efficient in LS patients who recover spontaneously from acute lung sarcoidosis.…”

Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

“…[1][2][3][4] Although most studies have focused on reconstitution of effector T cells, several studies have also examined recovery of CD4 regulatory T cells (CD4Tregs). [5][6][7][8][9] These studies suggest that CD4Treg deficiency can enhance alloreactivity and promote graftversus-host disease (GVHD). [10][11][12][13][14] Conversely, prompt recovery of CD4Tregs can prevent GVHD while also supporting recovery of a broad T-cell repertoire.…”