IL-7 and IL-15 Levels Reflect the Degree of T Cell Depletion during Lymphopenia and Are Associated with an Expansion of Effector Memory T Cells after Pediatric Hematopoietic Stem Cell Transplantation

Abstract

Differentially and functionally distinct T cell subsets are involved in the development of complications after allogeneic hematopoietic stem cell transplantation (HSCT), but little is known about factors regulating their recovery after HSCT. In this study, we investigated associations between immune-regulating cytokines, T cell differentiation, and clinical outcomes. We included 80 children undergoing allogeneic HSCT for acute leukemia using bone marrow or peripheral blood stem cells grafted from a matched sibling or unrelated donor. Cytokines (IL-7, IL-15, IL-18, SCF, IL-6, IL-2, and TNF-α) and active anti-thymocyte globulin (ATG) levels were longitudinally measured along with extended T cell phenotyping. The cytokine profiles showed a temporary rise in IL-7 and IL-15 during lymphopenia, which was strongly dependent on exposure to active ATG. High levels of IL-7 and IL-15 from graft infusion to day +30 were predictive of slower T cell recovery during the first 2 mo post-HSCT; however, because of a major expansion of memory T cell stages, only naive T cells remained decreased after 3 mo (p < 0.05). No differential effect was seen on polarization of CD4+ T cells into Th1, Th2, or Th17 cells or regulatory T cells. Low levels of IL-7 and IL-15 at day +14 were associated with acute graft-versus-host disease grades II–IV in ATG-treated patients (p = 0.0004 and p = 0.0002, respectively). Children with IL-7 levels comparable to healthy controls at day +14 post-HSCT were less likely to develop EBV reactivation posttransplant. These findings suggest that quantification of IL-7 and IL-15 may be useful as biomarkers in assessing the overall T cell depletion and suggest a potential for predicting complications after HSCT.

Anti‐thymocyte globulin‐mediated immunosenescent alterations of T cells in kidney transplant patients

“…However, plasma IL‐15 was comparable between ATG + and ATG − patients, and the correlation of IL‐15 level with the frequency of CD28 − T cells was observed only in ATG − patients (Figure 3d). Previous studies have shown that circulating IL‐15 rapidly increases within 2 weeks after ATG treatment or myeloablative conditioning and then gradually subsides 60,64 . Likely, the lymphopenia‐mediated elevation of IL‐15 had already subsided by the time we collected samples and the chronic inflammatory environment contributes to maintaining an elevated level of IL‐15 in both ATG + and ATG − patients.…”

“…Previous studies have shown that circulating IL-15 rapidly increases within 2 weeks after ATG treatment or myeloablative conditioning and then gradually subsides. 60,64 Likely, the lymphopenia-mediated elevation of IL-15 had already subsided by the time we collected samples and the chronic inflammatory environment contributes to maintaining an elevated level of IL-15 in both ATG + and ATG À patients. It should be noted that CD28 À T cells are more expanded in ATG + patients, regardless of the IL-15 concentration, than in ATG À patients, probably reflecting ATGmediated early elevation of IL-15 as described previously.…”

“…Further, IL-15 production can also be enhanced by inflammatory signals. 59,60 In haematopoietic cell transplantation, an increased level of IL-7 and IL-15 is linked to successful T-cell repopulation, although there is also an increased risk of acute graft versus host disease (GvHD) and relapse. 61,62 It has been well known that IL-15 is critical for antigen-independent expansion and survival of senescent CD28 À T cells.…”

“…It should be noted that CD28 À T cells are more expanded in ATG + patients, regardless of the IL-15 concentration, than in ATG À patients, probably reflecting ATGmediated early elevation of IL-15 as described previously. 60 Cytomegalovirus (CMV) infection is an important factor in post-transplant treatmentrelated morbidity and mortality. 65 The association between ATG therapies and CMV infection (primary or reactivation) as a result of delayed reconstitution of lymphocytes and prolonged time to absolute lymphocyte count recovery after ATG treatment has been previously reported.…”

“…Severe lymphopenic conditions cause an elevation of circulating IL‐7 and IL‐15 because of diminished consumption of these cytokines by lymphocytes expressing the relevant receptors. Further, IL‐15 production can also be enhanced by inflammatory signals 59,60 . In haematopoietic cell transplantation, an increased level of IL‐7 and IL‐15 is linked to successful T‐cell repopulation, although there is also an increased risk of acute graft versus host disease (GvHD) and relapse 61,62 .…”