PD‐L2 Inhibits Protective Immunity, Th2 Cell Functional Quality, and GATA‐3 Expression During Filarial Nematode Infection

Filarial nematodes infect over 200 million people, predominantly stimulating a Type 2 immune response. Protective immunity takes decades to become effective due to dominant immune suppression that develops during infection. Using Litomosoides sigmodontis infection as a murine model of filariasis, we previously demonstrated that PD‐1 co‐inhibition causes Th2 cells to become intrinsically dysfunctional or hypo‐responsive during infection, resulting in impaired protective immunity. Τhis study demonstrates that Th2 cell‐intrinsic hypo‐responsiveness is associated with a loss of GATA‐3 expression by CD4 + T cells from WT, but not PD‐L2 −/− mice. PD‐L2 −/− mice were more resistant to L. sigmodontis and had increased Th2 cell‐intrinsic functional quality. CD19 + B cells expressed PD‐L2, and Jh −/− B cell‐deficient mice were more resistant to infection. However, Th2 cell‐intrinsic hypo‐responsiveness still developed in Jh −/− mice, and restricting PD‐L2 deficiency to B cells using bone marrow chimaeras did not alter resistance to L. sigmodontis or Th2 cell‐intrinsic functional quality. Together, these data indicate that PD‐L2 inhibits protective immunity to L. sigmodontis , downregulates GATA‐3 in CD4 + T cells, and induces Th2 cell‐intrinsic hypo‐responsiveness. Whilst B cells play a suppressive role during infection, this is independent of PD‐L2 and B cells do not instigate Th2 cell‐intrinsic hypo‐responsiveness.