CD4+Foxp3+ Tregs suppress antitumor responses using a granzyme B–dependent mechanism while the regulatory control of GVHD by Tregs exploits a distinct mechanism that is granzyme B–independent.

Allogeneic bone marrow transplantation (BMT) is a viable therapeutic option for the treatment of a variety of hematologic malignancies. A major complication of allogeneic BMT is graft-versus-host disease (GVHD), in which the alloreactive T cells transferred along with the bone marrow graft respond to antigenic differences expressed on host tissues. Although this posttransplantation complication is a significant cause of morbidity and mortality after allogeneic BMT, GVHD does appear to have a significant antitumor benefit, often termed a graft-versus-leukemia (GVL) effect. Relapse rates in patients who develop GVHD are considerably lower compared with rates in patients who do not develop this complication after transplantation. Over the past several decades, attempts to identify and separate specific immune effector mechanisms that mediate GVHD and GVL have been largely unsuccessful. Sometimes the best way to make progress in a field is not to keep trying to get further down the same road, but to take the road less traveled. In this issue of Blood, Cai and colleagues have uncovered the fact that suppression of GVHD and GVL appear to function by different mechanisms.1  If these differences in the regulation of GVHD and GVL effector mechanisms can be exploited, the potential for therapeutic enhancement of allogeneic BMT for the treatment of hematologic malignancies is great.

Distinct pathways of CD4+Foxp3+ regulatory T cell–mediated suppression of GVHD and GVL.

Distinct pathways of CD4+Foxp3+ regulatory T cell–mediated suppression of GVHD and GVL.

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Cai et al evaluated the potential role and underlying mechanisms of CD4+Foxp3+ regulatory T cells (Tregs) in regulating GVHD after allogeneic BMT. These Tregs are known to play a critical role in maintaining peripheral tolerance to self-antigens by suppressing autoreactive immune effector functions. Tregs can also suppress the development of antitumor immunity, which, in fact, may be a consequence of maintaining peripheral tolerance. Tregs appear to function through a number of different mechanisms to suppress or control an immune response. can release immunoregulatory cytokines (IL-10, TGFβ) that can modify activated T cells and suppress the function of antigen-presenting cells. Another mechanism used by Tregs requires direct cell contact and engagement of CTLA-4 with CD80/86 costimulatory cell-surface receptors. Engagement of these receptors can inactivate the responding T cells and alter dendritic cell function. Regulatory T cells can also eliminate effector cells through a granzyme B/perforin-dependent cytolytic mechanism. Previous studies by this group led by Dr Timothy Ley revealed that CD4+Foxp3+Treg suppression of antitumor responses was granzyme B–dependent. In this setting, the antitumor immune effector T cells were eliminated through a cytolytic mechanism. In contrast, the present studies by Cai et al indicate that regulation of GVHD by Tregs was independent of granzyme B. The alloreactive T cells that mediate GVHD were suppressed by an alternate mechanism(s) used by the CD4+Foxp3+ Treg compartment (see figure). Interestingly, suppression of both GVL and GVHD immune responses required direct contact between regulatory and effector T cells.

The studies by Cai et al reveal that CD4+Foxp3+ Tregs appear to use distinct non-overlapping mechanisms to suppress GVHD and the antitumor response (GVL effect) after allogeneic BMT. Differential mechanisms of suppression may allow for the segregation of GVHD and GVL and provide the foundation to specifically modify different allotumor, autotumor, and antitumor immune responses by targeting distinct pathways of Treg-mediated suppression. Exploitation of these differential functional mechanisms holds great therapeutic promise. The decades-long struggle to enhance the antitumor response of allogeneic BMT while suppressing the graft-versus-host response finally may be in sight by exploring the road less traveled.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

Granzyme B is not required for regulatory T cell—mediated suppression of graft-versus-host disease.
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