CTLA-4 and CD4+CD25+ Regulatory T Cells Inhibit Protective Immunity to Filarial Parasites In Vivo

Abstract

The T cell coinhibitory receptor CTLA-4 has been implicated in the down-regulation of T cell function that is a quintessential feature of chronic human filarial infections. In a laboratory model of filariasis, Litomosoides sigmodontis infection of susceptible BALB/c mice, we have previously shown that susceptibility is linked both to a CD4+CD25+ regulatory T (Treg) cell response, and to the development of hyporesponsive CD4+ T cells at the infection site, the pleural cavity. We now provide evidence that L. sigmodontis infection drives the proliferation and activation of CD4+Foxp3+ Treg cells in vivo, demonstrated by increased uptake of BrdU and increased expression of CTLA-4, Foxp3, GITR, and CD25 compared with naive controls. The greatest increases in CTLA-4 expression were, however, seen in the CD4+Foxp3− effector T cell population which contained 78% of all CD4+CTLA-4+ cells in the pleural cavity. Depletion of CD25+ cells from the pleural CD4+ T cell population did not increase their Ag-specific proliferative response in vitro, suggesting that their hyporesponsive phenotype is not directly mediated by CD4+CD25+ Treg cells. Once infection had established, killing of adult parasites could be enhanced by neutralization of CTLA-4 in vivo, but only if performed in combination with the depletion of CD25+ Treg cells. This work suggests that during filarial infection CTLA-4 coinhibition and CD4+CD25+ Treg cells form complementary components of immune regulation that inhibit protective immunity in vivo.

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

“…The interference with regulatory T cell function in L. sigmodontis-infected BALB/c mice led to improved parasite clearance thus suggesting that indeed L. sigmodontis actively suppresses the immune response to itself (26)(27)(28). The power of this suppression was demonstrated by the fact that implantation of a single L. sigmodontis female adult into resistant DBA/1 mice inhibited the clearance of MF, which under normal circumstances occurs within 3 d in this mouse strain (29).…”

“…It is, however, conceivable that resident Treg had initiated suppressive circuits in the very beginning of the infection. Taylor et al (28) showed that depletion of Treg before infection with L. sigmodontis reduced worm burden 60 d later, whereas Treg depletion by application of anti-CD25 mAb alone at later time points of infection did not improve resistance (26,27). In this setting, it was necessary to additionally interfere with other regulatory pathways by application of anti-CTLA-4 (27) or anti-GITR mAb (26) to improve resistance.…”

“…To understand how the established L. sigmodontis infection mediated suppression of Th cells, we focused on Treg and IL-10 because there is accumulating evidence that these are central mediators of L. sigmodontis-induced suppression of the immune response toward itself (26)(27)(28)(29)43) and to third-party Ags (30-32, 44, 45) in different systems. Also, human studies strongly support the notion that IL-10 is a key mediator of nematode-induced immune suppression (46)(47)(48)(49).…”

Helminths and dendritic cells: Sensing and regulating via pattern recognition receptors, Th2 and Treg responses

“…To increase the chances of survival, parasitic worms have evolved to exploit this Achilles' heel of the immune system by promoting the induction and expansion of Treg responses that result in downregulation of Th2 effector responses against the parasites (reviewed in [2,3]). The importance of this mechanism for the survival of the parasite is exemplified by the fact that, after depletion of Treg or neutralization of their suppressor molecules, Th2 immunity and protection against the infection can be restored [121][122][123]. Although Treg responses are beneficial to the parasite, the promotion of this regulatory arm is thought to be important for the host as well, since in several helminth models IL-10-deficient mice display severe pathology and increased mortality as a result of an overt inflammatory response to the parasitic infection [124][125][126].…”

Inmunorregulación inducida por helmintos: una actualización

“…También se ha demostrado que los Treg inducidos por parásitos tienen capacidad inmunosupresora sobre otras poblaciones de linfocitos T (14). La secreción de IL-10 o TGF-β es un mecanismo inmunorregulador preponderante en algunas infecciones, al igual que la expresión de moléculas, como el antígeno 4 del linfocito T citotóxico (CTLA-4) o el miembro 19 de la superfamilia del receptor de factor de necrosis tumoral (GITR), que actúan mediante el contacto célula-célula (15,16).…”