CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress.
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 [(3)H]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 zeta-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.
Makarenkova
Valeriya P
VP
Department of Surgery, University of Pittsburgh Medical Center, PA 15213, USA.
Bansal
Vishal
V
Matta
Benjamin M
BM
Perez
Lori Ann
LA
Ochoa
Juan B
JB
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D039481:CD11b Antigen / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013312:Stress, Physiological / Q000503:physiopathology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014947:Wounds and Injuries
D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D007376:Interleukin-2; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D019707:Receptors, Chemokine; C054979:antigen T cell receptor, zeta chain; D001120:Arginine