Splenic CD8α⁺ dendritic cells undergo rapid programming by cytosolic bacteria and inflammation to induce protective CD8⁺ T‐cell memory

Abstract

Memory CD8+ T lymphocytes are critical effector cells of the adaptive immune system mediating long‐lived pathogen‐specific protective immunity. Three signals – antigen, costimulation and inflammation – orchestrate optimal CD8+ T‐cell priming and differentiation into effector and memory cells and shape T‐cell functional fate and ability to protect against challenge infections. While among the conventional spleen DCs (cDCs), the CD8α+ but not the CD8α− cDCs most efficiently mediate CD8+ T‐cell priming, it is unclear which subset, irrespective of their capacity to process MHC class I‐associated antigens, is most efficient at inducing naïve CD8+ T‐cell differentiation into pathogen‐specific protective memory cells in vivo. Moreover, the origin of the required signals is still unclear. Using mice infected with the intracellular bacterium Listeria monocytogenes, we show that splenic CD8α+ cDCs become endowed with all functional features to optimally prime protective memory CD8+ T cells in vivo within only a few hours post‐immunization. Such programming requires both cytosolic signals resulting from bacterial invasion of the host cells and extracellular inflammatory mediators. Thus, these data designate these cells as the best candidates to facilitate the development of cell‐based vaccine therapy.

Development, Homeostasis, and Heterogeneity of NK Cells and ILC1

“…These distinct profiles suggest that NK cells and ILC1 play different roles in immunity. It also highlights that in contrast to our current understanding, ILC1 probably kill target cells, albeit by mechanisms that differ from NK cells, and could be involved in regulatory roles either directly or indirectly via interactions with T cells (Campisi et al 2011;Fallarino et al 2004;Huang et al 2004;Terme et al 2012). …”

Therapeutic options for treatment of human papillomavirus-associated cancers - novel immunologic vaccines: ADXS11–001

“…Other advantages of Lm -LLO immunotherapies are their lack of induction of neutralizing antibodies and their capacity to facilitate chemotaxis of activated immune cells. Interestingly, Lm -LLO immunotherapies also stimulate robust immune memory responses; correlates of immune memory to Lm have been reported to develop just 5 h after exposure [58]. In various models, Lm -LLO immunotherapies have been shown to also induce therapeutic changes in the ratio of CD8-positive tumor-infiltrating lymphocytes to Tregs [59].…”

Mechanistic insights into ADXS11-001 human papillomavirus-associated cancer immunotherapy

“…In addition, bacteria that have escaped the phagosome into the cytosol may release antigenic fragments that are presented by MHC class I molecules to CD8+ cytotoxic T cells, with both CD4+ and CD8+ T cells involved in final clearance of the infection and generation of protective immunity [14, 15]. Lm is a strong stimulator of CD8+ T-cell responses in particular, with CD8+ T cells undergoing rapid programming to become long-lived CD8+ memory T cells, which provide protection against subsequent Lm infections [16]. Dendritic cells are an important link between the innate and adaptive immune responses, with their activation in response to the TLR signaling cascade required for co-stimulation of T cells and the effective activation of cell-mediated immunity [14, 16].…”

“…Lm is a strong stimulator of CD8+ T-cell responses in particular, with CD8+ T cells undergoing rapid programming to become long-lived CD8+ memory T cells, which provide protection against subsequent Lm infections [16]. Dendritic cells are an important link between the innate and adaptive immune responses, with their activation in response to the TLR signaling cascade required for co-stimulation of T cells and the effective activation of cell-mediated immunity [14, 16]. The CD8α subset of conventional dendritic cells is most effective in supporting this CD8+ T-cell memory formation [15].…”