Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 43, Issue 11, Pages 2930-2942Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201343349
Keywords
CD8(+) T-cell activation; CD8(+) T-cell suppression; Monocytic myeloid-derived suppressor cell (MO-MDSC); Nitric oxide; Polymorphonuclear MDSC (PMN-MDSC)
Categories
Funding
- FWO-Vlaanderen
- IWT-Vlaanderen
- Stichting tegen Kanker
- Vlaamse Liga tegen Kanker
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Tumor growth coincides with an accumulation of myeloid-derived suppressor cells (MDSCs), which exert immune suppression and which consist of two main subpopulations, known as monocytic (MO) CD11b(+)CD115(+)Ly6G(-)Ly6C(high) MDSCs and granulocytic CD11b(+)CD115(-)Ly6G(+)Ly6C(int) polymorphonuclear (PMN)-MDSCs. However, whether these distinct MDSC subsets hamper all aspects of early CD8(+) T-cell activation including cytokine production, surface marker expression, survival, and cytotoxicity is currently unclear. Here, employing an in vitro coculture system, we demonstrate that splenic MDSC subsets suppress antigen-driven CD8(+) T-cell proliferation, but differ in their dependency on IFN-, STAT-1, IRF-1, and NO to do so. Moreover, MO-MDSC and PMN-MDSCs diminish IL-2 levels, but only MO-MDSCs affect IL-2R (CD25) expression and STAT-5 signaling. Unexpectedly, however, both MDSC populations stimulate IFN- production by CD8(+) T cells on a per cell basis, illustrating that some T-cell activation characteristics are actually stimulated by MDSCs. Conversely, MO-MDSCs counteract the activation-induced change in CD44, CD62L, CD162, and granzyme B expression, while promoting CD69 and Fas upregulation. Together, these effects result in an altered CD8(+) T-cell adhesiveness to the extracellular matrix and selectins, sensitivity to FasL-mediated apoptosis, and cytotoxicity. Hence, MDSCs intricately influence different CD8(+) T-cell activation events in vitro, whereby some parameters are suppressed while others are stimulated.
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