T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response

Abstract

Background Treatments for autoimmune diseases aim to dampen autoreactivity while preserving normal immune function. In CD4 + T cells, the transcription factor Oct1/Pou2f1 is a dispensable transcription factor for T cell development and response to primary infection, but promotes expression of target genes, including Il2 and Ifng , under conditions of antigen reencounter. As a result, they are more strongly expressed upon secondary stimulation. Such repeated antigen encounters occur in memory recall responses, in autoimmunity where self-antigen can be recognized multiple times, and in chronic infection where foreign antigen is persistent. Based on these previous findings, we hypothesized that Oct1 loss would protect animals from autoimmunity but maintain normal responses to pathogens in the CNS. Objective We used a conditional mouse Oct1 ( Pou2f1 ) allele and a CD4-Cre driver to determine the effect of T cell-specific Oct1 loss on autoimmune- and viral-induced neuroinflammation using an autoantigen-driven EAE model of autoimmunity and a JHMV model of viral infection. Results Oct1 conditional deletion mitigated clinical scores and reduced infiltrating T cells and cytokine production in the EAE model. Consistently, Oct1-deficient CD4 + T cells stimulated in vitro showed increased expression of markers associated with T cell anergy, particularly in the absence of co-stimulatory signals. In contrast, anti-viral T cell effector functions are intact in the absence of Oct1, with no changes in neuroinflammation, infiltrating T cells or cytokine production. Conclusion Our findings uncover a significant difference between the effect of Oct1 loss on autoimmune and anti-pathogen responses, which potentially could be exploited for therapeutic benefit. Electronic supplementary material The online version of this article (10.1186/s12974-019-1523-3) contains supplementary material, which is available to authorized users.

Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

“…60-80% of female NOD mice develop T1D in standard environments (Makino et al, 1985). We find that prediabetic OCA-B T cell deficient NOD mice harbor normal T cell numbers and TCR specificities in their PLNs, consistent with prior observations that OCA-B deficient T cells are largely immunocompetent (Kim et al, 2019;Shakya et al, 2015). Nevertheless, T cell conditional OCA-B knockouts are protected from spontaneous T1D.…”

“…A whole body OCA-B knockout also reduces fat accumulation and insulin resistance in aged mice, likely through ablation of B cell-mediated inflammation in white adipose tissue (Carter et al, 2018). T cellspecific knockout of Oct1, a transcription factor with which OCA-B docks, blocks EAE but preserves responses to infection with neurotropic viruses (Kim et al, 2019). Together these data show that in T cells Oct1 and OCA-B promote autoimmunity including T1D, but that their role in B cells may be more complex.…”

“…Consistently, OCA-B loss promotes CD4 + T cell anergy in vitro. Loss of Oct1, the transcription factor with which OCA-B docks, also augments anergic responses (Kim et al, 2019). C57BL/6.RIP-mOVA and NOD.BDC2.5 transgenic mice are simplified monoclonal systems that allow tracking of uniform T cell responses to antigens in vivo (Haskins, 2005).…”

“…In CD4 + cells, ICOS (Inducible T-cell Costimulator) promotes the induction of T cell anergy (Dong et al, 2001;Dong and Nurieva, 2003;Tuettenberg et al, 2009) and is up-regulated by Oct1 loss in naïve T cells subjected to stimulation under anergic conditions (Kim et al, 2019). Oct1 loss also elevates expression of FR4 and CD73 (Kim et al, 2019) the co-expression of which is a marker for anergy (Kalekar et al, 2016;Martinez et al, 2012). To determine whether OCA-B loss similarly affects expression of these proteins, we stimulated naïve splenic CD4 + T cells (CD8a neg CD11b neg CD45R neg DX5 neg Ter-119 neg CD44 lo ) from 6 wk-old Ocab fl/fl CD4-cre and littermate control CD4-cre male NOD mice for 2 d ex vivo using anti-CD3e antibodies ± costimulation.…”

“…In contrast, Oct1 and OCA-B insulate silent but previously activated target genes against stable repression. Loss of either protein does not affect CD4 + T cell responses to stimulation in vitro or primary infection in mice (Kim et al, 2019;Shakya et al, 2015), but causes target gene expression defects upon secondary stimulation in vitro (Shakya et al, 2015;Shakya et al, 2011). Loss of either protein also results in defective CD4 + memory T cell formation and recall responses in vivo (Shakya et al, 2015).…”