NKG2D signaling certifies effector CD8 T cells for memory formation

Abstract

Background The development of memory responses is an evolutionary function of the adaptive immune system. We propose that for the immune system to populate the memory compartment with the best-suited CD8 T cells it utilizes a process of certification or molecular accreditation mediated through Natural Killer Group 2D (NKG2D). This process of certification assures that the memory compartment is filled with CD8 T cells that have demonstrated their ability to kill their cognate targets through a two-step process that utilizes T cell receptor (TCR) and NKG2D signaling. Methods One week after immunization with peptide-pulsed dendritic cells, NKG2D signaling was transiently blocked in vivo with a single injection of neutralizing antibodies. Under such conditions, we determined the importance of NKG2D signaling during the effector phase for memory formation without compromising NKG2D signaling at the memory phase . Both open (polyclonal) and closed (monoclonal) CD8 T cell repertoires were studied. Results We show that signaling through NKG2D mediated this certification. Temporary blockade of NKG2D signaling during the effector phase resulted in the formation of highly defective memory CD8 T cells characterized by altered expression of the ribosomal protein S6 and epigenetic modifiers, suggesting modifications in the T cell translational machinery and epigenetic programming. Finally, these uncertified memory cells were not protective against a B16 tumor challenge. Conclusion Signaling through NKG2D during the effector phase (certification) favors the development of functional memory CD8 T cells, a previously undescribed role for NKG2D. Temporary blockade of NKG2D signaling during the effector phase results in the formation of highly defective memory CD8 T cells potentially by affecting the expression of the ribosomal protein S6 and epigenetic modifiers, suggesting alterations in T cell translational machinery and epigenetic programming. Electronic supplementary material The online version of this article (10.1186/s40425-019-0531-2) contains supplementary material, which is available to authorized users.

Gene modification strategies for next-generation CAR T cells against solid cancers

“…Natural killer group 2 member D is a strong costimulatory receptor expressed on NK and CD8 + T cells [56]. It can transmit an activating signal in T cells, via the adaptor protein, DNAX-activating protein 10 (DAP10), leading to memory formation and enhanced inflammatory cytokine production in CD8 + T cells [57,58]. Thus, DAP10 incorporation into the 3′ end of CAR indeed improves the antitumor activity of CAR T cells against lung cancer, hepatocellular carcinoma, and gastric cancer in mouse models [59,60].…”

The Role of NKG2D in Vitiligo

“…Engagement of NKG2D on CD8 T cells in combination with IL-15 stimulation can trigger the killing of target cells, a feature of autoimmune diseases (39, 84, 95, 100-102). While NKG2D plays an important role in the effector phase of T cells, we have shown that engagement of this receptor also has longterm effects, including the promotion of memory formation (35). In the mentioned study, we show that signaling through NKG2D mediates a process that we termed memory certification.…”

“…Notably, studies from our group have established in animal models that NKG2D signaling also leads to the development of long-lasting CD8 T cells with enhanced cytolytic function (33)(34)(35). NKG2DL upregulation and NKG2D signaling activation in effector CD8 T cells play a role in the onset or development of some autoimmune diseases, including vitiligo, rheumatoid arthritis, celiac disease, type 1 diabetes, alopecia areata, systemic lupus erythematosus (SLE), among others (36)(37)(38)(39)(40)(41).…”

NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

“…Temporary blockade of NKG2D signaling in the effector phase resulted in development of altered defective memory CD8+ T cells, which means that uninterrupted NKG2D signaling in the effector phase promotes development of fully functional memory CD8+ T cells. This is a new feature of the NKG2D receptor [26].…”