Severe chronic graft-versus-host disease is characterized by a preponderance of CD4+ effector memory cells relative to central memory cells

Abstract

Donor alloreactive CD4 ؉ T cells are important to the pathogenesis of chronic graftversus-host disease (cGVHD), but specific subsets of CD4 ؉ T cells responsible for GVHD have not been defined. We hypothesized that cGVHD might be associated with a preponderance of CD4 ؉ effector memory cells (CCR7 ؊ /CD62L low , CD4 EM ). We analyzed CCR7 and CD62L expression on CD4 ؉ T cells from stem cell transplantation patients, who did or did not develop cGVHD, and healthy donors. Patients with cGVHD had a higher percentage of CD4 EM cells (35.5% ؎ 2.9%) than healthy donors (13.8% ؎ 0.7%; P < .0001) or patients without cGVHD that received a transplant (21.7% ؎ 2.1%; P < .01). Using corticosteroid dose as a surrogate marker for cGVHD severity, severe cGVHD was associated with a higher percentage of CD4 EM IntroductionChronic graft-versus-host disease (cGVHD) is the most common late complication of allogeneic stem cell transplantation. 1 Donorderived, alloreactive, postthymic CD4 ϩ T cells play an important role in pathogenesis of cGVHD, 2 however, the pathophysiology remains unclear.Human peripheral blood CD4 ϩ T cells can be divided into 3 populations: naive CD45RA ϩ CCR7 ϩ and 2 memory subsets, CD45RA Ϫ CCR7 ϩ (central memory) and CD45RA Ϫ CCR7 Ϫ (effector memory). Chemokine receptor CCR7 is pivotal for migration into secondary lymphoid organs. 3 Expression of CD62L (Lselectin), which also guides lymphocytes into lymphoid tissue, is tightly linked to CCR7 expression on memory CD4 ϩ T cells. 4 Central memory CD4 ϩ T cells are nonpolarized and retain the capacity to differentiate into either T-helper 1 (Th1) or Th2 when restimulated. Thus, they are effector precursors that regulate immune response. Conversely, effector memory cells are actively involved in inflammation and cytotoxicity. 5 When stimulated via T-cell receptor, central memory cells produce only interleukin 2 (IL-2). In contrast, effector memory cells produce high levels of interferon ␥ (IFN-␥), IL-4, and IL-5 and moderately reduced levels of IL-2 in vitro. 4 In healthy individuals, central memory CD4 ϩ T cells are predominant in peripheral blood. An imbalance of the central and effector memory CD4 ϩ T-cell ratio may result in autoimmune or alloimmune disease, but this has not been described.We examined expression of CCR7 and CD62L on CD4 ϩ T cells in cGVHD patients in order to characterize the balance of central and effector memory cells. Study designAll cGVHD patients received transplants using myeloablative or nonmyeloablative marrow conditioning from a 6 of 6 or 5 of 6 human leukocyte antigen (HLA)-matched related donor. All patients provided written informed consent for participation in a variety of institutional review board-approved NIH Clinical Center stem cell transplantation protocols.Fresh peripheral blood mononuclear cells (PBMCs) were obtained by Ficoll separation with lymphocyte separation medium (ICN Biomedicals Inc, Aurora, OH) from 36 adult healthy donors, 25 cGVHD patients, 20 patients after allogeneic stem cell transplantation without cGVHD...

Gene expression analysis of peripheral T cells in a subgroup of common variable immunodeficiency shows predominance of CCR7– effector-memory T cells

“…A recent report by Yamashita et al describes a predominance of CCR7 -cells among CD4 + T cells in patients with chronic graftversus-host-disease (cGVHD) [41]. cGVHD is associated with chronic antigenic stimulation, and intriguingly, some patients with cGVHD may present with hypogammaglobulinaemia [42].…”

Imbalance of effector and regulatory CD4 T cells is associated with graft-versus-host disease after hematopoietic stem cell transplantation using a reduced intensity conditioning regimen and alemtuzumab

“…The αβ T cells are principle players, and depletion of either CD4 or CD8 T cells can reduce clinical GvHD 4,5 but few studies have examined the role of T-cell subsets. Chronic GvHD has been associated with an increase in CD4 effector memory, 6 increase in CD8 central memory and decrease in CD4 central memory cells. 7 In acute GvHD, a correlation was found with prevalence of naïve and central memory CD4 T cells in the donor allograft.…”

Increase of CCR7− CD45RA+ CD8 T cells (TEMRA) in chronic graft-versus-host disease

“…1 Comparatively little is known about the role of CD8 T cells in cGVHD and whether, similarly to CD4 T cells, it is associated with the preponderance of a particular CD8 T-cell subset.…”

“…As Activating mutations of genes in the receptor tyrosine kinase RAS-BRAF (RTK/RAS-BRAF) signal transduction pathway are common in myelodysplasia (MDS) and acute myeloid leukemia (AML) [1][2][3][4] and in the therapy-related subsets of these diseases (t-MDS/t-AML). 5 Recently, a specific activating mutation of the JAK2 tyrosine kinase was detected in 154/201 cases of polycythemia vera (77%), in 21/44 cases of idiopatic myelofibrosis (48%) and in 50/144 cases of essential thrombocythemia (35%).…”