Initiation and regulation of effector T cell responses in the prostate

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells identified in mice as Gr-1CD11b cells with the ability to inhibit T cell function. MDSC are emerging as important regulators of T cell mediated immune responses. Current paradigm suggests that despite heterogeneity, all Gr-1CD11b cells are suppressive when exposed to inflammatory stimuli. In vitro evaluation shows MDSC from multiple tissue sites have suppressive activity, and in vivo inhibition of MDSC enhances T cell function. However, the relative capacity of MDSC present at localized inflammatory sites or in peripheral tissues to suppress T cell responses in vivo has not been directly evaluated. Using a tissue specific acute inflammatory prostatitis model, we demonstrate that MDSC inhibition of CD8 T-cell proliferation is restricted to the inflammatory site. Further, MDSC from inflammatory sites possess immediate capacity to inhibit T-cell function, whereas those isolated from peripheral tissues (spleens and liver) were not suppressive without activation of iNOS by exposure to IFN-γ. Using two mouse models of prostate cancer, we extend these findings to the tumor micro-environment. During a chronic inflammatory response induced by tumor growth, we show Gr-1CD11b cells from the tumor site possess immediate capacity to regulate effector T cell function whereas those from the spleen do not. In both tumor models and in our prostatitis model, long term culture of activated T cells with splenic Gr-1CD11b cells converted precursor cells into functional MDSC during standard in vitro suppression assays. These data highlight the importance of MDSC in the prostate, and demonstrate the function of MDSC during a localized inflammatory response is restricted to the site of an ongoing immune response.