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

Abstract

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.