No abstract

The gut microbiome elicits antigen-specific immunoglobulin G (IgG) at steady state that cross-reacts to pathogens to confer protection against systemic infection. The role of gut microbiome–specific IgG antibodies in the development of the gut microbiome and immunity against enteric pathogens in early life, however, remains largely undefined. In this study, we show that gut microbiome–induced maternal IgG is transferred to the neonatal intestine through maternal milk via the neonatal Fc receptor and directly inhibits Citrobacter rodentium colonization and attachment to the mucosa. Enhanced neonatal immunity against oral C. rodentium infection was observed after maternal immunization with a gut microbiome–derived IgG antigen, outer membrane protein A, or induction of IgG-inducing gut bacteria. Furthermore, by generating a gene-targeted mouse model with complete IgG deficiency, we demonstrate that IgG knockout neonates are more susceptible to C. rodentium infection and exhibit alterations of the gut microbiome that promote differentiation of interleukin-17A–producing γδ T cells in the intestine, which persist into adulthood and contribute to increased disease severity in a dextran sulfate sodium–induced mouse model of colitis. Together, our studies have defined a critical role for maternal gut microbiome–specific IgG antibodies in promoting immunity against enteric pathogens and shaping the development of the gut microbiome and immune cells in early life.

Immune checkpoint inhibitor (ICI) therapies that promote T cell activation have improved outcomes for advanced malignancies yet also elicit harmful autoimmune reactions. The T cell mechanisms mediating these iatrogenic autoimmune events remain unclear. Here we assayed T cells from joints of patients affected by ICI-induced inflammatory arthritis (ICI-arthritis), which can present clinically indistinguishable from rheumatoid arthritis (RA). Compared to the autoimmune arthritides RA and psoriatic arthritis (PsA), ICI-arthritis joints contained an expanded CD38hi CD127− CD8+ T cell subset that displays cytotoxic, effector, and interferon (IFN) response signatures. The abundance of CD38hi CD8 T cells in ICI-arthritis resulted from a limited number of clones that could be found proliferating in the joint. Exposure of synovial T cells to Type I IFN, more so than IFN-γ, induces the CD38hi cytotoxic phenotype. Relative to other CD8+ T cell subsets in the joints, the CD38hi population is distinct from a dysfunctional population and clonally most related to TCF7+ memory populations. Examination of synovial tissue from bilateral knee arthroplasty demonstrated considerable sharing of TCR clonotypes in the CD38hi CD8 T cell fraction from both knees. These results define a distinct CD8 T cell subset that may be directly activated by ICI therapy and mediate a tissue-specific autoimmune cellular reaction in patient joints.

BackgroundImmune checkpoint inhibitor (ICI) therapies that promote T cell activation have improved outcomes for advanced malignancies yet can also elicit harmful autoimmune reactions. The T cell mechanisms mediating these iatrogenic autoimmune events remain unclear.ObjectivesTo investigate the immunophenotype, transcriptomic feature and clonotypes of T cells from joints of patients affected by ICI-induced inflammatory arthritis (ICI-arthritis).MethodsDetailed immunophenotyping was performed on mononuclear cells from synovial fluid (SF) using mass cytometry and flow cytometry to identify significantly altered populations in ICI-A compared to seropositive rhrumatoid arthritis (RA) and psoriatic arthritis (PsA) (p<0.05). Bulk RNA-seq was performed on altered SF CD8 T cell subsets from ICI-A, RA and PsA to investigate their transcriptomic features. Cytokine profile and pathways enriched in ICI-A CD8 T cells were examined using differentially expressed genes, intracellular staining, and in vitro culture. TCR clonotypes were examined using single cell RNA-seq of T cells from synovial fluid, tissue and blood of ICI-A.ResultsCompared to the autoimmune arthritides RA and PsA, ICI-arthritis joints contained an expanded CD38hi CD127- CD8+ T cell subset that displays cytotoxic, effector, and interferon (IFN) response signatures. Exposure of synovial T cells to Type I IFN, more so than IFN-γ, induced the CD38hi cytotoxic phenotype. Single cell transcriptomic and T cell repertoire (TCR) analyses indicated that the abundance of CD38hi CD8 T cells in ICI-arthritis resulted from proliferation of a limited number of clones. The CD38hi population appeared distinct from dysfunctional T cells and clonally most related to TCF7+ memory populations. Comparison of synovial tissue from bilateral knees of the same patient demonstrated considerable sharing of TCR clonotypes among CD38hi CD8 T cells between the two joints. Further, TCR clonotypes expanded in synovial fluid of ICI-arthritis patients were detected in circulating T cells, and circulating CD38hi CD8 T cells are also expanded in ICI-arthritis patients.ConclusionThese results define a distinct CD8 T cell subset in the synovial fluid and in the circulation of patients with ICI-A that may be directly activated by ICI therapy to mediate a tissue-specific autoimmune response.Disclosure of InterestsNone declared.