TY - JOUR
T1 - Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation
AU - Kusmartsev, Sergei A.
AU - Li, Yu
AU - Chen, Shu Hsia
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2000/7/15
Y1 - 2000/7/15
N2 - Activation of T cells is a necessary step in the development of a specific antitumor immune response. In the present study, we evaluated the ability of Gr-1+ myeloid cells, derived from the bone marrow or spleen of tumor-bearing mice, to inhibit CD3/CD28-mediated T cell activation. Using flow cytometry, we found that growth of a murine colon carcinoma (MCA-26) induces a significant increase in the number of Gr-1+ and Gr-1+/Mac-1+ myeloid cells in both bone marrow and spleen of the tumor host. The proliferative response of T cells was dramatically decreased when naive T cells were activated by anti-CD3 and anti-CD28 Abs in the presence of a myeloid-enriched cell fraction derived from spleen or bone marrow of tumor- bearing mice vs the bone marrow of naive mice. Reversal of the inhibitory effect could be achieved by adding a combination of MnTBAP (manganese [III] tetrakis [4-benzoic acid]) porphyrin and L-NMMA (N(G)-monomethyl-L-arginine), a superoxide dismutase mimetic and inducible NO synthase inhibitor, respectively, or by depletion of the Gr-1-positive cells. IFN-γ, which is endogenously produced by CD3/CD28-stimulated naive T cells, is involved in induction of the inhibitory activity of myeloid cells. Importantly, when T cells pre-activated with anti-CD3 Abs were used as responder cells, the bone marrow- or spleen-derived Gr-1+ myeloid cells were unable to suppress CD3/CD28-induced T cell proliferation. Our findings suggest that one mechanism by which an increased number of immune suppressive Gr-1+ cells can induce T cell unresponsiveness or immune tolerance in tumor hosts could be through peroxynitrite production upon primary T cell activation.
AB - Activation of T cells is a necessary step in the development of a specific antitumor immune response. In the present study, we evaluated the ability of Gr-1+ myeloid cells, derived from the bone marrow or spleen of tumor-bearing mice, to inhibit CD3/CD28-mediated T cell activation. Using flow cytometry, we found that growth of a murine colon carcinoma (MCA-26) induces a significant increase in the number of Gr-1+ and Gr-1+/Mac-1+ myeloid cells in both bone marrow and spleen of the tumor host. The proliferative response of T cells was dramatically decreased when naive T cells were activated by anti-CD3 and anti-CD28 Abs in the presence of a myeloid-enriched cell fraction derived from spleen or bone marrow of tumor- bearing mice vs the bone marrow of naive mice. Reversal of the inhibitory effect could be achieved by adding a combination of MnTBAP (manganese [III] tetrakis [4-benzoic acid]) porphyrin and L-NMMA (N(G)-monomethyl-L-arginine), a superoxide dismutase mimetic and inducible NO synthase inhibitor, respectively, or by depletion of the Gr-1-positive cells. IFN-γ, which is endogenously produced by CD3/CD28-stimulated naive T cells, is involved in induction of the inhibitory activity of myeloid cells. Importantly, when T cells pre-activated with anti-CD3 Abs were used as responder cells, the bone marrow- or spleen-derived Gr-1+ myeloid cells were unable to suppress CD3/CD28-induced T cell proliferation. Our findings suggest that one mechanism by which an increased number of immune suppressive Gr-1+ cells can induce T cell unresponsiveness or immune tolerance in tumor hosts could be through peroxynitrite production upon primary T cell activation.
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U2 - 10.4049/jimmunol.165.2.779
DO - 10.4049/jimmunol.165.2.779
M3 - Article
C2 - 10878351
AN - SCOPUS:0034661719
VL - 165
SP - 779
EP - 785
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -