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Review
. 2022 Sep 12:13:1001129.
doi: 10.3389/fimmu.2022.1001129. eCollection 2022.

Non-cytotoxic functions of CD8 T cells: "repentance of a serial killer"

Mouhamad Al Moussawy  1   2 , Hossam A Abdelsamed  1   2   3
Affiliations
Review

Non-cytotoxic functions of CD8 T cells: "repentance of a serial killer"

Mouhamad Al Moussawy et al. Front Immunol. .

Abstract

Cytotoxic CD8 T cells (CTLs) are classically described as the "serial killers" of the immune system, where they play a pivotal role in protective immunity against a wide spectrum of pathogens and tumors. Ironically, they are critical drivers of transplant rejection and autoimmune diseases, a scenario very similar to the famous novel "The strange case of Dr. Jekyll and Mr. Hyde". Until recently, it has not been well-appreciated whether CTLs can also acquire non-cytotoxic functions in health and disease. Several investigations into this question revealed their non-cytotoxic functions through interactions with various immune and non-immune cells. In this review, we will establish a new classification for CD8 T cell functions including cytotoxic and non-cytotoxic. Further, we will discuss this novel concept and speculate on how these functions could contribute to homeostasis of the immune system as well as immunological responses in transplantation, cancer, and autoimmune diseases.

Keywords: CD8 T cells (CTLs); cross-talk; direct-; indirect-; non-cytotoxic.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Classification of CD8 T cells functions: Schema showing classification of these functions into cytotoxic and non-cytotoxic. The cytotoxic functions were further partitioned into direct (killing tumors or virally infected cells) and indirect (recruitment of immune cells to the site of infection, tumor vaccines, and B cell help in cancer, pathogen clearance and autoimmunity). The non-cytotoxic functions were classified into direct (degradation of viral proteins and inhibition of viral replication) and indirect (tissue repair and regeneration, protection of DCs, and homeostasis).
Figure 2
Figure 2
Cytotoxic functions of CD8 T cells: (A) Direct cytotoxicity: CD8 T cells release perforin and granzyme B through MHC-I/TCR axis in order to activate the apoptotic pathway in the target cells. Further, the interaction between FasR and FasL results in activation of caspases and eventually apoptosis (B) Indirect cytotoxicity: (a) In response to activation by antigen re-exposure and cytokine release, antigen-specific memory CD8 T cells release a wide range of cytokines and chemokines such as IFNγ, CCL3, and MCP1 that would help (b) recruit innate cells such monocytes and NK cells that in turn secrete CXCL9/10 in order to further (c) amplify the recruitment of memory CD8 T cells, activate of B cells, and DCs (not shown in the figure).
Figure 3
Figure 3
Direct non-cytotoxic effects of CD8 T cells: (A) HIV specific CD8 T cells (a) interact and recognize HIV infected CD4 cells via unknown receptor-ligand and (b) release CAF which (c) prevents the transcription and translation of HIV viral proteins and therefore prevents the propagation of viral progenies. (B) GzmB+ CD8 T cells cluster around the bodies of HSV-1 infected ganglionic neurons keeping the virus in latent phase by degrading viral proteins (ICP 4/27), which is essential for the viral shift to active phase. This role is mediated by perforin and granzyme B released by CD8 T cells.
Figure 4
Figure 4
Indirect non-cytotoxic functions of CD8 T cells: (A) In response to skeletal muscle injury, CD8 T cells infiltrate the necrotic area and release MCP-1 which in turn helps recruit reparative macrophages to the site of injury (B) Upon recognition of antigen presented by DCs, memory CD8 cells release TNFα, which in turn upregulates protease inhibitor 9 (PI-9, endogenous anti-granzyme B) in DCs protecting them from CTL killing (C) Upon TCR stimulation, memory T cells undergo a rapid transition from a quiescent to a highly activated and proliferating state which is mediated by IL-2 cytokine downstream TCR stimulation. The cross-talk between naïve and activated memory CD8 T cells results in acquisition of two main states by naïve CD8 T cells: (1) activated/memory (CD45RO+ CD69+) and (2) hybrid population between naïve and effector (CD45ROneg CD69+).
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