Requirement for CD70 in CD4(+) Th cell-dependent and innate receptor-mediated CD8(+) T cell priming

Dendritic cell (DC) conditioning by CD4(+) T cells, or via engagement of innate receptors, is thought to be essential for CD8(+) T cell priming. However, the molecular features that distinguish a conditioned DC from an unconditioned DC are poorly defined. In this study. we investigate the role of CD70, a member of the TNF superfamily that is expressed on activated DC, in CD4+ Th-dependent and -independent CD8(+) T cell responses. We demonstrate that CD70 is required for CD4(+) T cell-dependent priming of CD8(+) T cells as well as priming mediated by the viral signature, dsRNA. Accordingly, mice that were subjected to CD70 blockade during the primary response fail to generate a memory CD8(+) T cell response. Furthermore, we find that CD70 is dispensable for CD4(+) T cell expansion and help for B cells, thus suggesting a direct role for CD70 in CD8(+) T cell priming. Our results show that the innate and adaptive (CD4(+) T cells) arms of the immune system use a common signaling pathway in driving CD8(+) T cell responses and suggest that expression of CD70 on DC represents the hallmark of conditioned DC

Death receptor 3 is essential for generating optimal protective CD41 T-cell immunity against Salmonella

The TNF receptor superfamily member death receptor 3 (DR3) exacerbates Th2- and Th17-cell-mediated inflammatory and autoimmune conditions, yet no role in host defence has been reported. Here, we examined the role of DR3 during infection with Salmonella enterica serovar Typhimurium. Infection resulted in protracted expression of the DR3 ligand TL1A but not the related TNF superfamily proteins OX40L or CD30L. TL1A expression was localized to splenic F4/80+ macrophages where S. enterica Typhimurium replicates, and temporally coincided with the onset of CD4+-cell expansion. To address the relevance of the TL1A-DR3 interaction, we examined immune responses to S. enterica Typhimurium in mice lacking DR3. Infected DR3-/- mice harboured reduced numbers of antigen-experienced and proliferating CD4+ T cells compared with WT mice. Furthermore, the frequency of IFN-?+ CD4+ T cells in DR3-/- mice was lower throughout the time of bacterial clearance. Importantly, bacterial clearance, which is dependent on Th1 cells, was also impaired in DR3-/- mice. This defect was intrinsic to CD4+ T cells as evidenced by an increase in bacterial burden in RAG2-deficient mice receiving DR3-/- CD4+ T cells compared with WT CD4+-cell recipients. These data establish for the first time a role for DR3 in a host defence responce

Triggering of TNFRSF25 promotes CD8+ T-cell responses and anti-tumor immunity

TNFRSF25 is a member of the TNF receptor superfamily (TNFRSF) that binds to the TNF-like protein TL1A. Although recent studies have demonstrated a role for TNFRSF25 in regulating CD4+ T-cell responses, it remains to be determined if TNFRSF25 functions as a costimulatory receptor for CD8+ T cells. Here, we demonstrate that ectopic expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8+ T-cell-dependent manner and renders mice immune to a subsequent challenge with tumor cells. To gain further insight into the role of TNFRSF25 in CD8+ T-cell responses, we analyzed the effect of TNFRSF25 triggering on OT-I TCR transgenic T cells. We demonstrate that TNFRSF25 triggering in vivo with soluble TL1A promotes the proliferation and accumulation of antigen-specific CD8+ T cells as well as their differentiation into CTLs. Furthermore, we show that TNFRSF25 also functions as a costimulatory receptor for memory CD8+ T cells. Thus, TNFRSF25 triggering enhances the secondary expansion of endogenous antigen-specific memory CD8+ T cells. Our data suggest that TNFRSF25 agonists, such as soluble TL1A, could potentially be used to enhance the immunogenicity of vaccines that aim to elicit human anti-tumor CD8+ T cells

PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity

Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DCs). DC signals can be bypassed by CD27 agonists and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved bycombining with agonist anti-CD27 monoclonal antibodies (mAb).Experimental Design: the efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow-cytometry analysis were used to delineate mechanisms underpinning the observed synergy.Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFN-, TNF-α, granzyme B and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL-2 and Myc. However, division of labor was also apparent such that anti-PD-1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for anti-tumor immunity. Finally, we show that a clinically-relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human-CD27 transgenic mice.Conclusions: our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches cooperate for CD8+ T-cell activation

Suppression of the optokinetic reflex in human infants: implications for stable fixation and shifts of attention.

The ability of 1-, 2-, and 4-month-old infants to attend to a small, stationary visual target while a large background texture moved horizontally was assessed using electrooculography. The background texture, consisting of a randomly arranged field of dots or a set of vertically oriented stripes, was effective at all ages in eliciting the optokinetic reflex (OKR), which stabilizes gaze on a moving display. When the target, consisting of a red bar, was added to the center of the moving background display, it was effective in suppressing the OKR, except in 1-month-olds. Under monocular viewing conditions, background motion in the nasal-temporal direction was ineffective in eliciting robust OKR in 1- and 2-month-olds. These same infants presented with temporal-nasal background motion showed robust OKR equal to their OKR under binocular viewing conditions. However, the 2-month-olds showed OKR suppression only half as often as they did under binocular viewing conditions, and the 1-month-olds did not show OKR suppression. The 4-month-olds showed no nasal-temporal OKR asymmetry under monocular viewing conditions, and, like the 2-month-olds, OKR suppression was present about half as often as under binocular viewing conditions