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CD11b⁺/Gr-1⁺ Myeloid Suppressor Cells Cause T Cell Dysfunction after Traumatic Stress¹

Valeriya P. Makarenkova^*, Vishal Bansal^*, Benjamin M. Matta^*, Lori Ann Perez and Juan B. Ochoa^2,*

^* Department of Surgery and Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213

T cell dysfunction that occurs after surgery or trauma is associated with a poor clinical outcome. We describe that myeloid suppressor cells expressing CD11b⁺/Gr-1⁺ markers invade the spleen after traumatic stress and suppress T cell function through the production of arginase 1. We created a consistent model of traumatic stress in C57BL/6 mice to perform this work. A significant number of CD11b⁺/Gr-1⁺ cells expressing arginase 1 accumulated in T cell zones around the germinal centers of the white pulp of the spleen within 6 h of trauma and lasted for at least 72 h. Increased arginase activity and arginase 1 expression, along with increased [³H]arginine uptake, L-arginine depletion, and L-ornithine accumulation in the culture medium, were observed exclusively in CD11b⁺/Gr-1⁺ cells after traumatic stress. Flow cytometry revealed CD11b⁺/Gr-1⁺ as a heterogeneous myeloid suppressor cell also expressing low levels of MHC class I and II, CD80, CD86, CD31, and others. When compared with controls, trauma-induced CD11b⁺/Gr-1⁺ cells significantly inhibited CD3/CD28-mediated T cell proliferation, TCR -chain expression, and IL-2 production. The suppressive effects by trauma CD11b⁺/Gr-1⁺ cells were overcome with the arginase antagonist N-hydroxy-nor-L-arginine or extrasupplementation of medium with L-arginine. Poor Ag-presenting capacity of control and trauma-induced CD11b⁺/Gr-1⁺ cells was detected in allogeneic murine leukocyte reaction. This study demonstrates that CD11b⁺/Gr-1⁺ cells invade the spleen following traumatic stress and cause T cell dysfunction by an arginase-mediated mechanism, probably that of arginine depletion. Understanding the mechanism of immune suppression by these cells has important clinical implications in the treatment of immune dysfunction after trauma or surgery.

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