We utilize RNA-Seq and flow cytometry to further characterize the inhibited and stimulated T cell subsets. We demonstrate that IgG-ICs inhibit the proliferation and differentiation of one subset of naïve T cells but stimulate the division of another naïve-like subset. Here, we examined the effects of well-defined, soluble immune complexes on the phenotypes of human peripheral T cell subsets. Interestingly, however, experiments in a skin-graft-transplant model indicated that the role of FcγRIIb is independent of IgG antibodies ( 25). reported that FcγRIIb expression in a subset of effector-memory CD8+ T cells correlates with kidney transplant tolerance following withdrawal from immunosuppression ( 25). Other studies demonstrated that subsets of CD4+ and CD8+ T cells from HIV-infected patients express FcγRIIa and FcγRIIIa, respectively ( 23, 24). In different disease settings including cancer, certain subsets of CD4+ T cells have been reported to express FcγRIII, FcγRII, and/or FcγRI the ligation of these receptors were reported to enhance interferon-gamma production and cytotoxicity in a subset of human CD4+ T-cells ( 21, 22). (2014) reported that FcγRIIb is expressed on murine CD8+ memory T cells following bacterial or viral infection and that FcγRIIb engagement suppresses T cell in vivo cytotoxicity against peptide-loaded or virus-infected targets ( 20). Moreover, the expression of antibody receptors (canonical FcRs or nc-FcRs) on T cells is not widely recognized ( 5, 8– 10, 14– 19), and it is unknown whether encounter with ICs can directly impact T cell phenotypes. Natural killer and B cells express FcγRIIIa and FcγRIIb, respectively, while about 20% of the human population also express FcγRIIc on NK cells and potentially B cells ( 8, 9). While FcγRs are ubiquitous on myeloid cells, their expression on lymphocytes is more restricted. Engagement of FcγRI, FcγRIIa/c, or FcγRIIIa results in pro-inflammatory responses, whereas FcγRIIb is the sole inhibitory FcγR which plays a role in multiple processes including inhibition of BCR signaling, suppression of inflammation, and the internalization/removal of small ICs by sinusoidal liver endothelial cells ( 5, 13). Humans express six FcγRs: FcγRI, FcγRIIa/b/c, and FcγRIIIa/b. While FcγRs exclusively bind IgG Fc, non-canonical Fc receptors (nc-FcRs) including certain C-type lectins and mannose receptors, can also bind IgG Fc however unlike canonical FcRs, nc-FcRs are promiscuous and can interact with IgG, IgA, IgE, and/or IgM Fc ( 11, 12). IC-FcγR interactions can elicit inhibitory or stimulatory signals, contributing to the overall outcome of an immune response ( 8– 10). IgG ICs are naturally found in sera of healthy subjects, but their presence is often more pronounced in disease states including autoimmunity and cancer ( 2– 7).
When antibodies bind to multivalent antigens, they form immune complexes (ICs) decorated with multiple antibody molecules that can bind with high avidity to Fc gamma receptors (FcγRs) expressed on a wide variety of immune cells, triggering a plethora of well-characterized phenotypes essential for immune homeostasis. IgG is the most abundant antibody isotype in serum, and presently all full-length therapeutic antibodies contain an IgG subtype Fc domain ( 1). Our findings reveal how ICs can link humoral immunity and T cell function. Furthermore, we show that while IgG1-ICs do not profoundly inhibit the proliferation of memory T cells, IgG1-ICs suppress the production of granzyme-β and perforin in cytotoxic memory T cells.
Phenotypic analysis by multi-parameter flow cytometry and RNA-Seq were used to characterize the inhibited and stimulated T cells revealing that the inhibited subset presented immature features resembling those of recent thymic emigrants and non-activated naïve T cells, whereas the stimulated subset exhibited transcriptional features indicative of a more differentiated, early memory progenitor with a naïve-like phenotype. We demonstrate that IgG-ICs inhibit the proliferation and differentiation of a subset of naïve T cells but stimulate the division of another naïve-like T cell subset. Here, we examined the effects of well-defined, soluble immune complexes (ICs) on human peripheral T cells. Elevated levels of circulating immune complexes are associated with autoimmunity and with worse prognoses in cancer.
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