Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC

Abstract

The costimulatory TNFR family member GITR can provide important survival signals for CD8 T cells. However, little is known about the regulation of this pathway during a chronic infection. In this study, we show that GITR ligand (GITRL) is maximally induced on APCs at day 2 post–lymphocytic choriomeningitis virus (LCMV) clone 13 infection, but is downregulated to below baseline levels by day 8 postinfection (p.i.), and remains so at the chronic stage of infection. At its peak, GITRL expression is highest on macrophages, with lower expression on conventional and plasmacytoid dendritic cells. GITR expression was highest on T regulatory cells but was also detected on Th1 and LCMV-specific CD8 T cells at day 8 p.i. and was maintained at low, but above baseline levels at the chronic stage of LCMV infection. As GITRL was limiting at the chronic stage of infection, we investigated the potential of therapeutic stimulation of GITR at this stage using agonistic anti-GITR Ab. Anti-GITR treatment at day 21 p.i. increased the frequency and number of LCMV-specific CD8 T cells, resulting in increased in vivo CTL activity and a concomitant decrease in viral load, despite the persistence of PD-1 expression. These effects of anti-GITR were CD8 T cell intrinsic, with no detectable effects on Th1 or T regulatory cells. In contrast to other TNFR agonists, such as anti–4-1BB, which can cause immune pathology, a single therapeutic dose of anti-GITR did not induce splenomegaly or increase serum alanine transaminase. These studies identify GITR as a promising therapeutic target for chronic infection.

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

“…GITR activation is important for CD4 + and CD8 + T cell differentiation and expansion to control acute and chronic viral infections (Clouthier et al, 2014; Clouthier et al, 2015; Pascutti et al, 2015). In an acute influenza infection model, GITR expression in CD8 + T cells mediated T cell survival (Snell et al, 2010).…”

Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease

“…During chronic LCMV infection, mice genetically deficient in GITR experience more severe T cell exhaustion, fewer antigen specific CD8 T cells and higher viral loads (Clouthier et al, 2015). During chronic LCMV infection, the ligand for GITR is highly upregulated early in infection, but expression rapidly returns to low levels within a week, suggesting a potential role for this pathway normally early in infection rather than during the chronic phase (Clouthier et al, 2014). Mice constitutively expressing the ligand for GITR on APCs have significantly higher numbers of antigen specific CD8 T cells with better cytokine production by CD4 and CD8 T cells and lower viral load (Clouthier et al, 2014; Pascutti et al, 2015).…”

“…During chronic LCMV infection, the ligand for GITR is highly upregulated early in infection, but expression rapidly returns to low levels within a week, suggesting a potential role for this pathway normally early in infection rather than during the chronic phase (Clouthier et al, 2014). Mice constitutively expressing the ligand for GITR on APCs have significantly higher numbers of antigen specific CD8 T cells with better cytokine production by CD4 and CD8 T cells and lower viral load (Clouthier et al, 2014; Pascutti et al, 2015). Treatment with a single dose of a GITR agonist antibody during chronic infection produced a similar virological outcome without increased immunopathology (Clouthier et al, 2014).…”

Enhanced CD8 T Cell Responses through GITR-Mediated Costimulation Resolve Chronic Viral Infection

“…We found no differences in GITR expression in CD4 + or CD8 + T cells during LCMV infection (S5B Fig. ), which may be related to the upregulation of GITR on T cells following LCMV infection [51]. In conclusion, we postulate that GITR-mediated costimulation enhances CD8-mediated viral clearance by boosting the helper function of CD4 T cells.…”

“…This does not imply that GITR triggering on CD8 T cells does not play a role, but may be a reflection of the fact that CD8 T cells interact less with B cells compared to CD4 T cells. In fact, there is ample evidence from in vitro [26] and in vivo [49–51] experiments that GITR triggering has a stimulating role on the function of CD8 T cells (reviewed in [52]). Yet, the observation that protection to LCMV chronicity in GITRL tg mice was completely lost when CD4 T cells were depleted (Fig.…”