CD25 expression distinguishes functionally distinct alloreactive CD4⁺ CD134⁺ (OX40⁺) T-cell subsets in acute graft-versus-host disease

CD134 (OX40) is expressed on activated CD4⁺ donor T cells in allogeneic stem cell transplant recipients with acute graft-versus-host disease. The data presented here reveal that differential expression of CD25 by CD4⁺ CD134⁺ T cells allows separation of these activated cells into 2 phenotypically and functionally distinct alloreactive T-cell subsets. These subsets exhibit distinct tissue associations, with CD4⁺ CD134⁺ CD25^- T cells preferentially found in lymphoid tissues and CD4⁺ CD134⁺ CD25⁺ T cells located in lymphoid tissues and inflamed extralymphoid tissues. The CD25^- T-cell subset exhibited potent proliferative responses to both concanavalin A and allogeneic host leukocytes. By contrast, the CD25⁺ T-cell subset proliferated minimally in response to either treatment and inhibited alloantigen-induced proliferation of the CD25^- subset. Proliferative unresponsiveness associated with the CD25⁺ T-cell subset did not extend to cytokine secretion. When stimulated with alloantigen, both CD4⁺ CD134⁺ T-cell subsets responded by secreting interferon-γ and interleukin (IL)-10, and neither T-cell subset produced detectable levels of IL-2 or IL-4. Three-day treatment of the CD25⁺ T-cell subset with IL-2 restored the proliferative responsiveness of these cells to host alloantigens, suggesting that the proliferative unresponsiveness associated with this T-cell subset reflected a requirement for IL-2. The preferential tissue associations and distinct functional properties associated with these separable alloreactive CD4⁺ CD134⁺ T-cell subsets suggest that they participate differentially in clinical graft-versus-host disease.