Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 119, Issue 12, Pages 3774-3786Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI39692
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Funding
- NIH [R01 AI34495, 2R01 HL56067, R01 AI059715, DOD BC011057, R01 CA118116]
- H. Lee Moffitt Cancer Center
- NATIONAL CANCER INSTITUTE [P01CA142106, R01CA118116] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL056067] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI034495, R01AI059715, P01AI056299] Funding Source: NIH RePORTER
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When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relatively well preserved in the absence of PKC isoform theta (PKC theta), a key regulator of TCR signaling. In contrast, PKC theta was required for alloreactivity and GVHD induction. Furthermore, absence of PKC theta raised the threshold for T cell activation, which selectively affected allo-responses. Most importantly, PKC theta-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKC theta is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.
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