TYK2:p.Pro1104Ala variant protects against autoimmunity by modulating immune cell levels

The TYK2 :p.Pro1104Ala (rs34536443) hypomorph variant has been associated with protection against numerous autoimmune disorders. Thus, its mechanism of action becomes of great interest. Here, consistent with the participation of activated immune cells in autoimmunity, we show that the variant regulates the levels of immune cells, and is associated particularly with higher levels of T and B lymphocytes, and especially the naïve (non-activated) compartment. Also, consistent with a protective function in autoimmunity, regulatory CD4+ T cell level was increased. Thus, this variant decreases the immune activation, protecting from autoimmunity. Our work identifies the cellular mechanism regulated by the TYK2 :p.Pro1104Ala variant and supports TYK2 as a therapeutic target in autoimmunity.