Comparison of microglia and infiltrating CD11c+ cells as antigen presenting cells for T cell proliferation and cytokine response

Abstract

BackgroundTissue-resident antigen-presenting cells (APC) exert a major influence on the local immune environment. Microglia are resident myeloid cells in the central nervous system (CNS), deriving from early post-embryonic precursors, distinct from adult hematopoietic lineages. Dendritic cells (DC) and macrophages infiltrate the CNS during experimental autoimmune encephalomyelitis (EAE). Microglia are not considered to be as effective APC as DC or macrophages.MethodsIn this work we compared the antigen presenting capacity of CD11c+ and CD11c− microglia subsets with infiltrating CD11c+ APC, which include DC. The microglial subpopulations (CD11c− CD45dim CD11b+ and CD11c+ CD45dim CD11b+) as well as infiltrating CD11c+ CD45high cells were sorted from CNS of C57BL/6 mice with EAE. Sorted cells were characterised by flow cytometry for surface phenotype and by quantitative real-time PCR for cytokine expression. They were co-cultured with primed T cells to measure induction of T cell proliferation and cytokine response.ResultsThe number of CD11c+ microglia cells increased dramatically in EAE. They expressed equivalent levels of major histocompatibility complex and co-stimulatory ligands CD80 and CD86 as those expressed by CD11c+ cells infiltrating from blood. CD11c+ microglia differed significantly from blood-derived CD11c+ cells in their cytokine profile, expressing no detectable IL-6, IL-12 or IL-23, and low levels of IL-1β. By contrast, CD11c− microglia expressed low but detectable levels of all these cytokines. Transforming growth factor β expression was similar in all three populations. Although CNS-resident and blood-derived CD11c+ cells showed equivalent ability to induce proliferation of myelin oligodendrocyte glycoprotein-immunised CD4+ T cells, CD11c+ microglia induced lower levels of T helper (Th)1 and Th17 cytokines, and did not induce Th2 cytokines.ConclusionsOur findings show distinct subtypes of APC in the inflamed CNS, with a hierarchy of functional competence for induction of CD4+ T cell responses.

Tertiary Lymphoid Tissue Forms in Retinas of Mice with Spontaneous Autoimmune Uveitis and Has Consequences on Visual Function

“…We also detected macrophages and microglia (Supplemental Fig. 1), both of which are able to act as antigen presenting cells, (26, 31–33) as well as FoxP3 + /CD4 + T cells, which are likely to represent regulatory T cells (Supplemental Fig. 2).…”

Metastatic site-specific polarization of macrophages in intracranial breast cancer metastases

“…Thus, to compare MAMs and microglia between dural and parenchymal metastases, we analyzed the expression of MHCII and CD11c, markers that have been previously associated with the APC phenotype in microglia/macrophages [30, 31]. In line with studies from glioma and other non-cancerous CNS disorders [31, 32], flow cytometry analysis showed that only a small percentage of parenchymal microglia expressed MHCII or CD11c independent of the breast cancer model (range 3–30% and 2–6.5%, respectively; Figure 2D–2E, Supplementary Figure S4B, Supplementary Figure S5A–S5B). In the 4T1 and PyMT models, the proportion of MHCII-expressing MAMs was significantly higher in dural versus parenchymal metastases (84–92% versus 56–78%).…”

Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE

“…cytokine production). Several reports have suggested that CNS-infiltrating DCs may be crucial APCs for in situ restimulation of T cells (Bailey et al, 2007, Bartholomaus et al, 2009, Greter, Heppner, 2005, Odoardi et al, 2007, Pesic et al, 2013, Wlodarczyk et al, 2014). For example, several studies using in vivo imaging studies have shown that T cells encounter and form stable interactions with perivascular phagocytes prior to their infiltration of the CNS parenchyma (Bartholomaus, Kawakami, 2009, Odoardi, Kawakami, 2007, Pesic, Bartholomaus, 2013).…”

“…For example, several studies using in vivo imaging studies have shown that T cells encounter and form stable interactions with perivascular phagocytes prior to their infiltration of the CNS parenchyma (Bartholomaus, Kawakami, 2009, Odoardi, Kawakami, 2007, Pesic, Bartholomaus, 2013). Ex vivo T cell activation assays demonstrated that CD11b+ CD11c+ myeloid DCs are the most potent CNS APCs (Bailey, Schreiner, 2007), and a recent study demonstrated that while CD11c+ microglia express MHC II during EAE they do not license T cells to become Th1 and Th17 effectors cells (Wlodarczyk, Lobner, 2014). Subsequent studies have shown that CD11c+ cell MHCII expression is both sufficient (Greter, Heppner, 2005) and required (manuscript in preparation) for T cell restimulation in situ.…”