To further ensure that MDSC directly developed T cell inhibitory properties as a result of persistent inflammation, we assessed IMC isolated from the bone marrow of colitis mice and subjected them to co-culture with activated healthy T splenocytes. As seen from our data, IMC developed T cell inhibitory properties as early as 3d, and the effectiveness of acquired inhibitory function steadily increased through the entire inflammatory DSS treatment, peaking at the early phase of inflammation resolution. Perhaps, most striking was the complete T cell proliferation suppression in the artificial-activation system mediated entirely by MDSC isolation from
inflammation recovery time points (12d-21d). This suppression was seen for both CD4+ and CD8+
T cells, and mirrors the in vivo data, demonstrating most significant T cell suppression during the same time points. These data confirms that T splenocyte populations are indeed being reduced as a direct function of MDSC accumulation in vivo, and that MDSC are most potent inhibitors of T cell function during the tissue repair process. Taken together, these data supports the
immunomodulatory role for MDSC at the adaptive immune effector cell level.
T cell inhibitory function within the spleen can be seen from our in vivo FACS data, which shows as MDSC collect in the spleen, T splenocyte populations dramatically decrease.
Interestingly, MDSC formation begins very early during the inflammatory response, before the insult moves to the post-acute phase of colitis; however, these suppressive MDSC are unable to mobilize into the circulation. Thus, the immunosuppressive capabilities of MDSC are reserved for times of truly persistent, unresolving inflammation. This system allows the immune system to develop a suppressive subtype of myeloid cells, which are only able to exert their suppressive function during times of persistent inflammatory activation, but not during acute, resolving inflammatory conditions. If inflammatory signals subside quickly, MDSC are not able to migrate out into circulation, and thus are unable to inhibit the immune response; however, if inflammatory signals persist to a point where potently suppressive myeloid cells are required to modulate immune function for the protection of the host, then suppressive myeloid cells gain the ability to enter circulation and carry out suppression of the immune response.
4.5 MDSC Function as Inhibitors of the Inflammatory Response During Chronic
Inflammation
In the past, MDSC have been discussed primarily as a harmful, immunosuppressive subtype of cells responsible for enabling tumor immune escape. As seen from our study, we determined a suppressive, non-pathogenic role for MDSC during colitis. As described in our study, we determined that MDSC first acquire T cell suppressive functions that peak at the post- acute stage of colitis inflammation, and that these cells remain sequestered away from T cells in the bone marrow until inflammation persists to the post-acute phase. Our study, in conjunction with other studies, demonstrated that soluble factors produced at the site of inflammation drive these functional changes within the bone marrow. Additionally, previous studies by our lab have described a role for IL-17 in the potentiation of PMN function. In this study, we propose IL-17 also functions to induce the generation of an immunosuppressive subtype of IMC which function
to coordinate resolution of persistent colitis inflammation by inhibiting the expansion of activated T cells. Our model describes a non-pathogenic evolutionary function of MDSC for the control of hyperactivation of the inflammatory response.
Since their discovery in tumor-bearing hosts, MDSC have primarily been studied in the context of cancer models that predominantly examine the specific methods MDSC use to induce immunosuppression, but these studies tend to neglect the naturally-evolved, non-pathogenic role of MDSC; however, expanded MDSC populations have also been reported as essential for the control of immune clearance of foreign tissue during allograft transplantation and pregnancy. During allograft transplantation, MDSC colonize the transplanted tissue and induce tolerance of the allograft, leading to decreased risk of rejection by the immune system of the recipient [127]. Similarly, during pregnancy, MDSC protect the “non-self” fetal tissue from clearance by the type I immune response by inducing tolerance, and helping to generate regulatory T cells [101]. Using the limited information regarding the non-pathogenic functions of MDSC during necessary immune suppression, we proposed that MDSC develop suppressive capabilities as a result of prolonged inflammation as a protective immune inhibitory feedback mechanism. As in pregnancy, MDSC-mediated non-pathogenic inhibition of the immune response is meant to protect the inflamed tissue from additional damage brought on by continuous activation of the
inflammatory response. As mentioned in the introduction, recruitment of mature inflammatory effector leukocytes to the site of inflammation results in secretion of many toxic, cell-damaging factors. The infiltration of PMN during inflammation secretes these cytotoxic factors in an effort to eliminate pathogen from sites of non-sterile injury, however these functions are non-specific to pathogen and result in the accumulation of damaged cells within the tissue. During progression to the post-acute phase of colitis, the accumulation of epithelial cell damage results in loss of gut
barrier function, which induces more inflammation that is unable to resolve in the tissue. In this system, inhibition of the type I immune response to pathogen is essential for the resolution of inflammation. Generation of anti-inflammatory, immunosuppressive myeloid cells function to inhibit the inflammatory response to stop the recruitment of tissue-damaging leukocytes, and to promote the transition toward inflammation resolution and tissue repair