Coinfection withHeligmosomoides polygyrusFails To Establish CD8⁺T-Cell Immunity againstToxoplasma gondii

Abstract

CD8؉ T-cell immunity is important for long-term protection against Toxoplasma gondii infection. However, a Th1 cytokine environment, especially the presence of gamma interferon (IFN-␥), is essential for the development of primary CD8؉ T-cell immunity against this obligate intracellular pathogen. Earlier studies from our laboratory have demonstrated that mice lacking optimal IFN-␥ levels fail to develop robust CD8 ؉ T-cell immunity against T. gondii. In the present study, induction of primary CD8؉ T-cell immune response against T. gondii infection was evaluated in mice infected earlier with Heligmosomoides polygyrus, a gastrointestinal worm known to evoke a polarized Th2 response in the host. In the early stage of T. gondii infection, both CD4 and CD8؉ T-cell responses against the parasite were suppressed in the dually infected mice. At the later stages, however, T. gondii-specific CD4 ؉ T-cell immunity recovered, while CD8 ؉ T-cell responses remained low. Unlike in mice infected with T. gondii alone, depletion of CD4 ؉ T cells in the dually infected mice led to reactivation of chronic infection, leading to Toxoplasma-related encephalitis. Our observations strongly suggest that prior infection with a Th2 cytokine-polarizing pathogen can inhibit the development of CD8 ؉ T-cell immune response against T. gondii, thus compromising long-term protection against a protozoan parasite. This is the first study to examine the generation of CD8 ؉ T-cell immune response in a parasitic nematode and protozoan coinfection model that has important implications for infections where a CD8 ؉ T-cell response is critical for host protection and reduced infection pathology.

Cutting Edge: Helminth Coinfection Blocks Effector Differentiation of CD8 T Cells through Alternate Host Th2- and IL-10–Mediated Responses

“…Consistent with this observation, the frequency of IFNγ positive cells among tetramer-binding CD8 T cells is markedly decreased in coinfected mice (Figure 1B, C and D). In addition, the overall incidence of IFNγ-producing CD8 T cells is also depressed by helminth coinfection (Figure 1B), recapitulating the effects seen by Khan and colleagues(18). …”

“…Khan and colleagues have previously shown that when mice are first infected with H. polygyrus 7 days prior to live T. gondii cyst challenge, polyclonal CD8 T cells fail to respond by IFNγ production (18). Nevertheless, it was unclear whether this defect reflected a helminth-imposed inhibition of cytokine production or a complete blockade in the priming and activation of T. gondii -reactive CD8 T cells.…”

IL-4 Attenuates Th1-Associated Chemokine Expression and Th1 Trafficking to Inflamed Tissues and Limits Pathogen Clearance

“…Thus, for many chronic infections (and tumors [18]), the central (LN) generation of protective Th1 immunity may be sufficient to control infection but local IL-4-rich tissue microenvironments prevent their recruitment and limit anti-microbial function [30]. This may be particularly destructive in the setting of co-infection [30], [32], [67], [68], [69], [70], [71]. Understanding the molecular events that are negatively regulated by IL-4 will be essential for the design of novel therapeutics that target chronic infection by inhibiting IL-4's control of immunity in tissues.…”

Toxoplasma Co-infection Prevents Th2 Differentiation and Leads to a Helminth-Specific Th1 Response

“…At later stages the T. gondii -specific CD4 + T cell response recovers whereas the CD8 + response remains disrupted (Khan et al, 2008). In line with this, other studies have shown that prior infection with H. polygyrus induced suppression of IL-12 dependent differentiation of effector CD8 + T cells as well as IFN-γ production against T. gondii .…”