TNF-α antagonists provide benefit to patients with inflammatory autoimmune disorders such as Crohn’s disease, rheumatoid arthritis, and ankylosing spondylitis. However, TNF antagonism unexplainably exacerbates CNS autoimmunity, including multiple sclerosis and neuromyelitis optica. The underlying mechanisms remain enigmatic. We demonstrate that TNFR2 deficiency results in female-biased spontaneous autoimmune CNS demyelination in myelin oligodendrocyte glycoprotein–specific 2D2 TCR transgenic mice. Disease in TNFR2−/− 2D2 mice was associated with CNS infiltration of T and B cells as well as increased production of myelin oligodendrocyte glycoprotein–specific IL-17, IFN-γ, and IgG2b. Attenuated disease in TNF−/− 2D2 mice relative to TNFR2−/− 2D2 mice identified distinctive roles for TNFR1 and TNFR2. Oral antibiotic treatment eliminated spontaneous autoimmunity in TNFR2−/− 2D2 mice to suggest role for gut microbiota. Illumina sequencing of fecal 16S rRNA identified a distinct microbiota profile in male TNFR2−/− 2D2 that was associated with disease protection. Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male TNFR2−/− 2D2 mice. In contrast, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female TNFR2−/− 2D2 mice, suggesting a role in disease causation. Overall, TNFR2 blockade appears to disrupt commensal bacteria–host immune symbiosis to reveal autoimmune demyelination in genetically susceptible mice. Under this paradigm, microbes likely contribute to an individual’s response to anti-TNF therapy. This model provides a foundation for host immune–microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders.

Summary The double-edged sword nature by which IL-2 regulates autoimmunity and the unpredictable outcomes of anti-TNF therapy in autoimmunity highlight the importance for understanding how TNF regulates IL-2. Transmembrane (tm) TNF preferentially binds TNFR2 while soluble (s) TNF binds TNFR1. We have previously shown reduced IL-2 production in TNFR1−/− TNFR2−/− CD4+ T cells. Here, we generated TNFR1−/−, TNFR2−/−, or TNFR1−/− TNFR2−/− 5C.C7 TCR Il2-GFP mice and report that CD4+ T cell-intrinsic tmTNF/TNFR2 stimulates Il2 promoter activity and Il2 mRNA stability. We further utilize tmTNF Foxp3 GFP reporter mice and pharmacological TNF blockade in wild-type mice to report a tmTNF/TNFR2 interaction for Il2 expression. IL-17 is critical for host defense but its overabundance promotes autoimmunity. IL-2 represses Th17 differentiation but the role for TNFR2 in this process is not well understood. Here, we report elevated expression of TNFR2 under Th17 polarization conditions. Genetic loss-of-function experimental models as well as selective TNF blockade by etanercept and XPro™1595 in wild-type mice demonstrate that impaired tmTNF/TNFR2, but not sTNF/TNFR1, promotes Th17 differentiation in vivo and in vitro. Under Th17 polarizing conditions, elevated IL-17 production by TNFR2 KO CD4+ T cells was associated with increased STAT3 activity and decreased STAT5 activity. Increased IL-17 production in TNFR2 KO T cells was prevented by adding exogenous IL-2. We conclude that CD4+ T cell-intrinsic tmTNF/TNFR2 promotes IL-2 production that inhibits the generation of Th17 cells in a FoxP3-independent manner. Moreover, under Th17 polarizing conditions, selective blockade of CD4+ T cell-intrinsic TNFR2 appears to be sufficient to promote Th17 differentiation.

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Tumor necrosis factor (TNF) plays dualistic pro-inflammatory and immune suppressive roles that lead to unpredictable outcomes of TNF blockade in autoimmune disease. Recent evidence has identified contrasting co-stimulatory effects of TNF on effector T cells and regulatory T cells in controlling autoimmunity. The objective of this study was to determine whether CD4+ T cell autonomous TNFR1 and TNFR2 differentially regulate IL-2 production. We utilize B10.A 5C.C7 TCR Tg Rag2-/- IL-2-GFP reporter mice that are deficient for TNFR1 and/or TNFR2 and memTNFΔ1-12 FoxP3-GFP reporter mice that encode an uncleavable tmTNF to demonstrate that TNFR2, but not TNFR1, and membrane, but not soluble, TNF promote Il2 promoter activity and decrease Il2 mRNA decay to increase IL-2 production in response to CD4+ T cell stimulation. We further demonstrate differential DNA binding of NF-κB in TNFR1- and TNFR2-deficient CD4+ T cells following activation. Adoptive transfer of naive CD4+ T cells from TNFR2-deficient IL-2-GFP heterozygous (IL-2+/-), but not IL-2-GFP homozygous (IL-2-/-), 5C.C7 Rag2-/- TCR Tg mice into B10.A Rag2-/- hosts and subsequent immunization with MCC88-103 + LPS yielded greater IL-17 production upon CD4+ T cell re-challenge in comparison to transfer of TNFR2-sufficient 5C.C7 TCR CD4+ T cells. Taken together, these results suggest that selective blockade of TNFR2 on CD4+ T cells is sufficient to inhibit IL-2 production and promote TH17 differentiation.