A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression

Abstract

Prolonged exposure of CD8+ T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8+ T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα+ CD8+ T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα+ cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8+ T cell-killing in vivo. SIRPα+ CD8+ T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8+ T cells during chronic infection expands the cytotoxic subset of SIRPα+ CD8+ T cells.

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

“…Our findings show that low DCLK1 expression correlated with high or low CD8 + T cells predicts better survival in colon and stomach cancer patients, suggesting DCLK1 has the potential to be an adjuvant target to promote sensitivity in immunotherapy-resistant patients. Additionally, it is widely reported that exhausted CD8+ T cells also express CD8A but lose the ability to eradicate the tumor cell [86,87]. This is hypothesized to be one significant reason why immune blockade increases the function of exhausted CD8+ T cells [88,89].…”

SIRPα on mouse B1 cells restricts lymphoid tissue migration and natural antibody production

“…Recently, SIRP was also reported to be selectively expressed on a small subset of T lymphocytes, i.e. exhausted CD8+ memory T cells emerging after chronic viral infection (Myers et al, 2019). For a long time the general assumption has been that SIRP is, at least among hematopoietic cells, restricted to the myeloid lineage (Adams et al, 1998;Brooke et al, 1998).…”

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

“…As a consequence most FVspecific CD8+ T cells appear functionally exhausted and are very inefficient in killing peptide-labeled targets in vivo (Zelinskyy et al 2009a). However, a small subset of functional CD8+ T cells are preserved even in chronic infection and uniquely express the cell surface protein SIRPα (Myers et al 2019). CD8+ T cell exhaustion contributes to the subsequent development of FV chronicity , similar to what has been described for chronic LCMV infection (Barber et al 2006).…”

“…During chronic infection PD-1 expression can be used as a surrogate marker for exhausted CD8+ T cells and blocking the signaling of this receptor with antibodies can reactivate exhausted T cells (Barber et al 2006;Dietze et al 2013). Blocking the PD-1/PDL-1 axis results in the expansion of functional CD8+ T cells that express SIRPα (Myers et al 2019). Increased expression of co-inhibitory molecules such as PD-1 is likely to prevent immunopathogenic effects from overstimulated CD8+ T cells responses.…”

“…The combination of chronic antigen stimulation and suppression by Tregs and MDSCs establishes an immunosuppressive milieu that presents a complicated therapeutic situation. During the chronic phase of infection, the cytotoxic and cytokine-mediated antiviral activities of effector CD8+ T cells are largely incapacitated (Zelinskyy et al 2005;Zelinskyy et al 2009a), although recent results indicate that a small subset of CD8+ T cells expressing SIRPα remains functional (Myers et al 2019). Thus, immunotherapy in chronic viral infection mainly aims to restore the functionality of virusspecific T cells or expand the functional subsets.…”