CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential

Abstract

CD8 T cells play crucial roles in immune surveillance and defense against infections and cancer. After encountering antigenic stimulation, naïve CD8 T cells differentiate and acquire effector functions, enabling them to eliminate infected or malignant cells. Traditionally, cytotoxic T cells, characterized by their ability to produce effector cytokines and release cytotoxic granules to directly kill target cells, have been recognized as the constituents of the predominant effector T-cell subset. However, emerging evidence suggests distinct subsets of effector CD8 T cells that each exhibit unique effector functions and therapeutic potential. This review highlights recent advancements in our understanding of CD8 T-cell subsets and the contributions of these cells to various disease pathologies. Understanding the diverse roles and functions of effector CD8 T-cell subsets is crucial to discern the complex dynamics of immune responses in different disease settings. Furthermore, the development of immunotherapeutic approaches that specifically target and regulate the function of distinct CD8 T-cell subsets holds great promise for precision medicine.

Fig. 1. The roles of Tc subsets in diseases.

Tc subsets play diverse roles in different diseases. Tc1 cells are known for their cytotoxic activity against tumors and infected cells, while Tc2 cells have been implicated in the pathogenesis of allergic diseases and cancer. Tc17 cells have been studied in the context of skin inflammation and the tumor microenvironment, while Tc9 cells have been associated with certain autoimmune disorders and antitumor effects. The role of Tc22 cells has been reported in psoriatic skin and tumor tissue. Tfcs support humoral responses in autoimmunity and are also found in the tumor microenvironment. Additionally, regulatory cell subsets such as CD8⁺ Foxp3⁺ Tregs, Qa1-restricted CD8⁺ Tregs and human KIR⁺ CD8⁺ Tregs have been identified in graft-versus-host disease and autoimmune diseases, in which they presumably contribute to immune regulation.

Fig. 2. Comparison of Th cell and Tc subsets.

Th cell subsets and Tc subsets share signal 3 cytokines, lineage-determining transcription factors, and effector cytokine profiles. Tc1 cells can be differentiated under IL-12 conditions and produce IFNγ through activation of the transcription factors T-bet, Eomes and STAT4. Tc2 cells can be differentiated under IL-4 conditions and produce IL-4, IL-5 and IL-13 through GATA-3 and STAT6. Tc9 cells can be differentiated under IL-4 plus TGF-β conditions and produce IL-9 through IRF-4 and STAT6. Tc17 cells can be differentiated under IL-6 plus TGF-β conditions through RORγt and STAT3. Tc22 cells can be differentiated under IL-6 plus TNF-ɑ conditions and produce IL-22 and TNF-ɑ through AhR, STAT1, STAT3 and STAT5. Tfcs can be differentiated under IL-6, IL-21, and IL-23 plus TGF-β conditions through BCL-6, TCF-1, E2A and Runx3. Foxp3⁺ CD8⁺ Tregs can be differentiated under TGF-β conditions and produce IL-10 and TGF-β through Foxp3. Qa-1-restricted CD8⁺ Tregs recognize the Qa-1 peptide on MHC class I molecules and suppress Qa-1-expressing T cells by secreting perforin meditated through the Eomes signaling pathway.

Fig. 3. Plasticity among Tc subsets.

Tc17 cells, akin to Th17 cells, display high plasticity in terms of cytokine production under specific conditions, and conversely, other Tc subsets can transform into Tc17 cells within certain contexts. Adoptive transfer of in vitro differentiated Tc17 cells led to their production of IFN-γ and granzyme B, similar to Tc1 cells. CTLA-4 plays a role in shifting the programming of Tc1 cells toward Tc17 cell differentiation. In the skin, alarmins such as IL-1, IL-18, and IL-33 stimulate commensal bacteria-specific Tc17 cells to produce Tc2 cytokines. Tc17 cells and Tc22 cells exhibit shared features, including similar differentiation-inducing cytokines, signaling transcription factors and cytokine production profiles. In a GvHD model, some adoptively transferred Foxp3⁺CD8⁺ Tregs were transformed into Tc17 and Tc1 cells. In addition to Tc17 cells, constituting another Tc subset also exhibit plasticity. Tc1 cells can produce IL-10 and exhibit suppressive functions in the context of viral infection. Tc2 and Tc9 cells share common features, including differentiation-inducing cytokines, signaling transcription factors and cytokine production profiles. In the tumor microenvironment, Tc9 cells undergo conversion to Tc1 cells, leading to potent antitumor immune responses, whereas Tc2 cells do not significantly contribute to attenuated tumor development.

Fig. 4. Controversial role of Tc17 cells in the tumor microenvironment.

Tc17 cells in the tumor microenvironment play distinct roles in tumor growth depending on their origin. ① In vitro-generated Tc17 cells are converted to effector Tc1 cells and repress tumor cell growth. On the other hand, Tc17 cells generated in vivo have been shown to exhibit pro-tumorigenic effects. ② Tc17 cells induced in the tumor microenvironment followed by CD4 depletion to recruit infiltrating myeloid cells and accelerate the exhaustion of effector Tc1 cells. ③ Tc17 cells from cancer patients presented with a terminally exhausted phenotype, which resulted in impaired antitumor immune responses.

Fig. 5. Types of suppressive CD8⁺ Tregs.

Suppressive CD8⁺ Tregs are distinguished by the expression of Foxp3. Qa-1-restricted CD8⁺ T cells and KIR⁺ human CD8⁺ T cells do not express Foxp3. Qa-1-restricted CD8⁺ T cells recognize the Qa-1 peptide on MHC class I molecules of autoreactive Tfh cells and suppress autoimmune diseases. Suppressive human CD8 T cells express KIR, which is the genetic counterpart of the Ly49 molecule in mice, and suppress autoreactive CD4 T cells that can cause tissue damage in autoimmune disorders. Foxp3-expressing CD8 T cells are activated in an early GVHD model in vivo and can be converted into IFN-γ and IL-17A-producing CD8 T cells.