Pathogen-encoded evasion of CXCL10 and T cell responses

Clearance of intracellular pathogens, such as Leishmania (L.) major, depends on a well-regulated adaptive T cell response. Here we describe a pathogen-encoded mechanism to alter T cell recruitment by suppressing CXCL10, a chemokine that recruits CD4+ and CD8+ T cells by signaling through the CXCR3 receptor. L. major suppresses CXCL10 through the virulence factor and protease, glycoprotein-63 (gp63). GP63 cleaves CXCL10 after amino acid A81, impairing T-cell chemotaxis in vitro. GP63 from either extracellular promastigotes or intracellular amastigotes is capable of cleaving CXCL10. Consistent with CXCL10 cleavage during infection, we observed GP63-mediated impairment of activated CD8+ T-cells in the draining lymph nodes of C57BL/6JWT mice. Correspondingly, in C57BL/6JWT mice, gp63 deletion resulted in slower lesion development and a smaller maximum lesion size. However, infection in C57BL/6Jcxcr3-/- mice revealed the delay to lesion development required CXCR3 signaling. Finally, Salmonella enterica and Chlamydia trachomatis infection also suppress CXCL10, demonstrating convergent evolution of this immune evasion strategy in diverse intracellular pathogens. Understanding mechanisms of CXCL10 evasion may facilitate the development of novel therapeutic strategies to treat intracellular pathogens.