A dominant function of LynB kinase in preventing autoimmunity

Here, we report that the LynB splice variant of the Src-family kinase Lyn exerts a dominant immunosuppressive function in vivo, whereas the LynA isoform is uniquely required to restrain autoimmunity in female mice. We used CRISPR-Cas9 gene editing to constrain lyn splicing and expression, generating single-isoform LynA knockout (LynA(KO)) or LynB(KO) mice. Autoimmune disease in total Lyn(KO) mice is characterized by production of antinuclear antibodies, glomerulonephritis, impaired B cell development, and overabundance of activated B cells and proinflammatory myeloid cells. Expression of LynA or LynB alone uncoupled the developmental phenotype from the autoimmune disease: B cell transitional populations were restored, but myeloid cells and differentiated B cells were dysregulated. These changes were isoform-specific, sexually dimorphic, and distinct from the complete Lyn(KO)) . Despite the apparent differences in disease etiology and penetrance, loss of either LynA or LynB had the potential to induce severe autoimmune disease with parallels to human systemic lupus erythematosus (SLE).

Automated summary

This study reveals the distinct immunological functions of different splice variants of the Lyn kinase in vivo. LynB isoform exerts a dominant immunosuppressive function, while LynA isoform is uniquely required to restrain autoimmunity in female mice. Through gene editing, single-isoform LynA or LynB knockout mouse models were generated, showing isoform-specific and sexually dimorphic regulation of immune cell development and autoimmune diseases.