CD31 Is Required on CD4+ T Cells To Promote T Cell Survival during Salmonella Infection

Abstract

Haematopoietic cells constitutively express CD31/PECAM1 a signalling, adhesion receptor associated with controlling responses to inflammatory stimuli. Although expressed on CD4+ T cells, its function on these cells is unclear. To address this we have used a model of systemic Salmonella infection that induces high levels of T cell activation and depends upon CD4+ T cells for resolution. Infection of CD31-deficient (CD31KO) mice demonstrates that these mice fail to control infection effectively. During infection, CD31KO mice have diminished numbers of total CD4+ T cells and IFN-γ-secreting Th1 cells. This is despite a higher proportion of CD31KO CD4+ T cells exhibiting an activated phenotype, and an undiminished capacity to prime normally and polarize to Th1. Reduced numbers of T cells reflected the increased propensity of naive and activated CD31KO T cells to undergo apoptosis after infection compared to wild-type (WT) T cells. Using adoptive transfer experiments we show that loss of CD31 on CD4+ T cells alone is sufficient to account for the defective CD31KO T cell accumulation. These data are consistent with CD31 helping to control T cell activation as in its absence T cells have a greater propensity to become activated, resulting in increased susceptibility to become apoptotic. The impact of CD31 loss on T cell homeostasis becomes most pronounced during severe, inflammatory and immunological stresses such as those caused by systemic Salmonella infection. This identifies a novel role for CD31 in regulating CD4 T cell homeostasis.

An immunologist's guide to CD31 function in T-cells

“…Tumor and skin allograft Enhanced tumor and skin allograft rejection (Ma et al, 2010) Systemic Salmonella infection Delayed pathogen clearance despite increased T-cell activation due to enhanced T-cell susceptibility to AICD (Ross et al, 2011) Generation of endothelial cell barrier in vitro Loss of endothelial barrier integrity (Privratsky et al, 2011) that CD31-deficient target cells are more susceptible to T-cellmediated cytotoxicity. The enhanced expansion of CD31-deficient T-cells, however, was accompanied by an increased activation-induced cell death (AICD) of CD31-deficient T-cells.…”

“…The lack of CD31 expression did not affect the magnitude of Tcell responses to antigen re-challenge (Ma et al, 2010). A recent study investigated the role of CD31-mediated interactions in T-cell protection against AICD in a model of Salmonella infection in CD31-deficient mice and described a delayed pathogen clearance, despite increased T-cell activation (Ross et al, 2011). T-cell activation subsequent to infection appears to be continuous and leads to an enhanced inappropriate susceptibility of CD31-deficient T-cells to AICD.…”

“…T-cell activation subsequent to infection appears to be continuous and leads to an enhanced inappropriate susceptibility of CD31-deficient T-cells to AICD. However, this increased apoptosis at the earliest stages of activation delays but does not abrogate pathogen clearance caused by the increased proliferative capacity of CD31-deficient T-cells, which eventually leads to a slow accumulation of activated T-cells (Ross et al, 2011). In addition to reducing AICD indirectly (i.e.…”

Absence of Platelet Endothelial Cell Adhesion Molecule 1, PECAM-1/CD31,In VivoIncreases Resistance to Salmonella enterica Serovar Typhimurium in Mice

“…As we have shown that PECAM-1 can bind to Salmonella adhesins, it would be interesting to further explore the role of PECAM-1 in Salmonella uptake by macrophages and dendritic cells. In this context, it is noteworthy that Ross et al found that at least in in vitro experiments, adherent splenic cells from wild-type and PECAM-1 Ϫ/Ϫ mice infected with S. Typhimurium contain comparable numbers of intracellular bacteria (28). Indeed, while PECAM-1 may play a role in uptake of Salmonella by phagocytic cells, there are likely other receptors involved.…”

“…Additional experiments using systemic infection routes are warranted to further address whether this diminished spread explains why PECAM-1-deficient mice are less susceptible to S. Typhimurium infection. However, others have shown that following intraperitoneal infection with an attenuated strain of S. Typhimurium, PECAM-1 deficiency results in delayed clearance of Salmonella infection as a result of impaired T-cell responses (28). However, the initial establishment of infection and bacterial loads during the early-phase response, which is known to be T-cell independent, were not altered (29).…”