Butyrophilin 2A2 promotes T cell immunoregulation via CD45 phosphatase activation and protects against murine autoimmune... 2026 Karumanchi et al

[Andy]

Full title: Butyrophilin 2A2 promotes T cell immunoregulation via CD45 phosphatase activation and protects against murine autoimmune glomerulonephritis and pregnancy loss

Abstract​

B7 costimulatory family member Butyrophilin 2A2 (BTN2A2) is predominantly expressed by antigen presenting cells and regulates T cell immunity, but molecular mechanisms are unclear. Using immunoblots analyzing TCR-initiated signaling intermediaries, co-immunoprecipitation studies, confocal microscopy, structural modeling-guided mutational analyses, and microscale thermophoresis, we demonstrate that BTN2A2 directly interacts with CD45RO, resulting in CD45 retention within the immune synapse during TCR activation. Recombinant BTN2A2 increases murine CD4+Foxp3+ regulatory T cells (Treg) and reduces T helper 17 (Th17) cells in vitro through mechanisms dependent on CD45 phosphatase activity. BTN2A2 therapy alleviates disease severity in murine nephrotoxic glomerulonephritis and autoimmune miscarriage while increasing Treg/Th17 ratios. Analyses of BTN2A2-deficient animals show exacerbation of disease associated with reduced Treg/Th17 ratios. BTN2A2 functions analogously on human T cells suppressing Th17, Th1 and Th2 responses while inducing Tregs. Together, our studies identify BTN2A2 as a modulator of CD45RO signaling in T cells, providing insight into how BTN2A2 regulates T cell-dependent immune responses including those mediating autoimmunity and transplant rejection.

Open access

 

[Jonathan Edwards]

I don't know if anyone knows what to predict from the ME/CFS linked "BTN2A2" SNP but it would be intriguing if ME/CFS risk was the price paid for being resistant to a spectrum of autoimmune disease. Maybe the DQ finding is real and even the HLA-C7 and the absent autoimmune haplotype.

 

[V.R.T.]

the HLA-C7 and the absent autoimmune haplotype

Im not sure I'm aware of either of these connections?

 

[Jonathan Edwards]

Im not sure I'm aware of either of these connections?

Fluge and Mella made the interesting observation that ME/CFS seemed to be less common inpeople with the so-called autoimmune haplotype A1, B8, Dr3, which also includes a C allele, (maybe 7, but there are subtypes I think). HLA-C came up in the Zhang/Hansen paper. DecodeME seemed to find the same negative association with the haplotype at first but this turned out to be due to an error of calculation involving the imputation process (don't ask me). The DQ statistic stayed significant but by then we had all got cold feet about DQ because it is notorious for artefacts.

I think we are hoping to see direct HLA A,B,C,D allele analyses from DecodeME in due course. I assume that that may clarify things.