Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells

Abstract

Chronic graft-versus-host disease (cGVHD) is characterized by a state of profound immunodeficiency in association with alloreactive and autoimmune phenomena. These observations indicate an impairment of immunologic tolerance that could involve both central and peripheral mechanisms. Defective thymic function may contribute to dysregulation of central tolerance, but few studies have addressed peripheral tolerance. Recently a population of CD4 ؉ CD25 ؉ T cells (T reg cells) has been characterized, which controls immunologic reactivity in vivo and which on transfer can prevent experimental acute GVHD. We investigated the number and function of peripheral blood CD4 ؉ CD25 high T cells in patients more than 100 days after allogeneic hematopoietic stem cell transplantation. Patients with cGVHD had markedly elevated numbers of CD4 ؉ CD25 high T cells as compared to patients without GVHD. CD4 ؉ CD25 high T cells derived from patients in both groups were of donor origin, lacked markers of recent activation, and expressed intracellular CD152. In contrast to controls, CD4 ؉ CD25 high T cells derived from patients with cGVHD were characterized by lower surface CD62L expression. In vitro, CD4 ؉ CD25 high T cells were hyporesponsive to polyclonal stimulation and suppressed the proliferation and cytokine synthesis of CD4 ؉ CD25 ؊ cells, an effect that was independent of interleukin 10. These results indicate that chronic graft-versus-host injury does not occur as a result of T reg cell deficiency. IntroductionChronic graft-versus-host disease (cGVHD) remains the most frequent complication following allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 30% to 70% of long-term survivors. 1 Profound immune dysregulation leads to both immunodeficiency and autoimmunity, suggesting defects in central or peripheral immunologic tolerance. 2 Impairment of thymic function observed in patients with cGVHD 3 could lead to the release into the periphery of T cells with autoreactive potential. 4 Although such perturbations in central tolerance may be important, data relating to experimental autologous GVHD induction 5 or to models in which thymic, negative selection is prevented, 6 suggest that autoreactive T cells only induce tissue injury when there are additional defects in peripheral tolerance.Recently a population of naturally occurring regulatory CD4 ϩ T cells (T reg cells) that constitutively express the ␣ chain of the receptor for interleukin 2 (IL-2; CD25) has been characterized that can suppress immune responses both in vitro and in vivo (for reviews, see Maloy and Powrie, 7 Shevach, 8 and Wood and Sakaguchi 9 ). In humans, T reg cells appear to be enriched within the 1% to 2% of peripheral blood CD4 ϩ T cells that are CD25 high10 and in vitro, inhibit the function of effector T cells via a mechanism that requires prior T-cell activation, involves cell-to-cell contact, and is independent of cytokine secretion. [11][12][13][14][15][16] In contrast, in vivo studies indicate that cytokines such as IL-10 or transfor...

Global Natural Regulatory T Cell Depletion in Active Systemic Lupus Erythematosus

“…To check the expansion of self-directed effector cells, it appears important that the immune system could maintain, or if necessary, amplify the level of the Treg subpopulation. Over the course of a graftvs-host reaction, for example, patients appear capable of amplifying their Treg subpopulation in an appropriate manner (59). In the case of SLE, in contrast, the homeostatic control mechanisms of the Treg population appear to be profoundly perturbed.…”

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

“…Even though it is well known that Treg cells can prevent both aGVHD (Hoffman et al, 2002;Taylor et al, 2002;Edinger et al, 2003) and cGVHD (Zheng et al, 2004;Kim et al, 2005), little is known regarding their involvement in the pathogenesis of cGVHD versus aGVHD. In human cGVHD, there is evidence showing that Treg cells are positively associated with cGVHD (Clark et al, 2004), although contradictory data have been reported more recently (Miura et al, 2004). There is also circumstantial evidence that Treg cells are involved in the conversion of aGVHD to cGVHD; aGVHD has been shown to progress into cGVHD by rapamycin (Blazar et al, 1999) which is highly effective in inducing the proliferation of Treg cells in vitro (Battaglia et al, 2005).…”

Immunohistochemical and FISH analyses identify synovitis associated with chronic GVHD after allogeneic hematopoietic SCT

“…9 These data were not confirmed by another report, which showed an increase in Tregs in subjects with cGVHD. 10 In conclusion, synovitis as a manifestation of cGVHD is a rare, but clinically relevant, condition. Accurate and early diagnosis is required for timely and appropriate treatment of the disease.…”