Pascale Cracco

Naïve subset develops the most important alloreactive response among human CD4+ T lymphocytes in human leukocyte antigen-identical related setting.

In longitudinal clinical studies, receiving a high percentage of allogeneic donor‐derived CD4+CCR7+ T cells, which include naïve and central memory subsets have been correlated with increased incidence and severity of acute GVHD. Whether naïve and central memory CD4+ T‐cell subsets contribute more or equally to alloimmune responses are still unclear in human. The aim of this study was to investigate in vitro the alloreactive response of purified naïve, central memory, and effector memory CD4+ T‐cell subsets in HLA identical setting. By coculturing monocyte‐derived dendritic cells and purified CD4+ T‐cell subsets, from healthy HLA‐identical male and female sibling pairs, we found that naïve CD4+CCR7+CD45RA+ T cells developed the highest proliferative response upon stimulation by minor histocompatibility antigens and were progressively driven to produce high levels of interferon‐γ, tumor necrosis factor, and interleukin‐6. Comparatively, the central memory CD4+CCR7+CD45RAneg subset proliferated to a lower extent and produced very low amounts of pro‐inflammatory cytokines while the CCR7neg effector memory CD4+ subset was unresponsive. This study demonstrates the superior capacity of naïve CD4+ T cells to mount a primary alloreactive response as compared to central memory T cells. Their proliferative response associated with a pro‐inflammatory differentiation makes them potentially acute GVHD inducers. These in vitro results in line with what we have observed in clinical studies and may also lend support to approaches of partial selective T‐cell depletion for GVHD prevention.

Immune reconstitution following myeloablative allogeneic hematopoietic stem cell transplantation: the impact of expanding CD28negative CD8+ T cells on relapse.

Allogeneic stem cell transplantation has become standard therapy for hematologic malignancies through the positive immunologic graft-versus-leukemia effect. Initial immune recovery relies on peripheral expansion of infused T cells, which switch to a memory-like phenotype. This study prospectively investigated whether changes in subset composition precedes complications after myeloablative HLA-matched transplantation for hematologic malignancies. Of 80 allograft recipients, 18 were still free of clinical complication throughout 395 to 1564 days of follow-up. Compared with this complication-free subgroup, patients who developed chronic graft-versus-host disease (cGVHD) without relapsing recovered similar numbers of circulating T cells with predominance of CD8+ T cells lacking CC-chemokine receptor-7 and CD28 expression throughout the first year after transplantation. Conversely, poor CD8+ T cell recovery with diminished numbers of CD28neg CD8+ T cells (approximately 1/4th of that of relapse-free patients) preceded occurrence of malignant relapse. In multivariate analysis, lower CD28neg CD8+ T cell counts by day 60 postallograft were associated with a greater risk of subsequent relapse (hazard ratio [HR] 0.33; 95% confidence interval [CI]: 0.14-0.76; P = .01). Enumeration of CD28neg CD8+ T cells in patients could assist in predicting risk of relapse and help build an algorithm for accelerating the immune recovery by reducing the immunosuppressive treatment and considering the introduction of preemptive donor lymphocyte infusions.