T cells in health and disease

Abstract

T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4⁺ and CD8⁺ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4⁺ helper and CD8⁺ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4⁺ and CD8⁺ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4⁺ and CD8⁺ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8⁺ T cell differentiation trajectory, CD4⁺ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.

Fig. 1

Overview of thymocyte development and regulatory mechanism. T cell development experiences three key steps: T cell lineage commitment, β-selection, and CD4/CD8 lineage choice, where T cells undergo sequential developmental stages from TSPs to DN, DP, and SP. ETPs (DN1) possess the potential to differentiate into B cells, myeloid cells, and innate-type of T cells, while DN3 can differentiate into γδ T cells. Induced by Notch signaling, transcription factors TCF-1, GATA-3, and Bcl11b play critical roles in promoting T cell lineage commitment by limiting other lineage differentiation. A pre-TCR complex consisting of TCRβ, pTα, and CD3 molecules on DN3 enforces β-selection and DN3 to DN4 development. Both pre-TCR and Notch signaling play critical roles in driving β-selection and DN to DP transition. Following positive and negative selection in the thymic cortex and medulla, respectively, DP cells differentiate into either CD4⁺ SP under the regulation of strong TCR and Thpok or CD8⁺ SP under the regulation of weak TCR and Runx3

Fig. 2

Cytokine signalings regulate CD4⁺ Th cell differentiation. Upon TCR stimulation, naïve CD4⁺ T cells can be differentiated into distinct effector Th subsets under different cytokines and costimulatory stimulation. IFN-γ and IL-12 drive Th1 cell differentiation by inducing the master TF T-bet expression through STAT1 and STAT4, respectively. Th2 cells are induced by TCR-stimulated TCF-1 activation and cytokine IL-2 and IL-4 signaling, expressing key TF GATA-3. Th9 cells are induced under TCR stimulation in the presence of IL-4 and TGF-β, and enhanced development by STAT5 activation. While IL-6 and TGF-β drive Th17 cell differentiation, IL-21 and IL-23 stabilize Th17 lineage by inducing RORγt. Cytokines IL-6 and IL-21 promote, while IL-2 inhibits Tfh cell differentiation. Costimulatory signaling from CD28 and ICOS play opposite roles in Tfh cell development. T_reg cells can be differentiated upon TCR/CD28 stimulation in the presence of TGF-β and IL-2 through inducing Foxp3 expression. Shared cytokines are illustrated between cells: IL-4 for Th2 and Th9, TGF-β for Th9 and Th17, IL-6 for Th17 and Tfh, and IL-2 for Tfh and T_reg cells. The same cytokines may induce different downstream signaling cascade and differentiation fate. For instance, IL-6-induced STAT3 activation leads to the expression of RORγt in Th17 cells but Bcl-6 in Tfh cells. Signaling complexes formed are indicated in the dashed squares

Fig. 3

Temporal dynamics of CD8⁺ T cell response in acute infection. The population size of the virus (red line) and CD8⁺ T cells (blue line), as well as CD8⁺ T cell response along with the infection course, are indicated. Upon infection, CD8⁺ T cells undergo robust proliferation and reach the expansion peak on day 8, where the pathogens are rapidly cleared. CD8⁺ T cells at this stage can be separated into T_E and T_MP populations with distinct surface marker and differentiation potential. The differentiation of effector and memory CD8⁺ T cells is regulated by different transcriptional factors and cytokines. The majority of CD8⁺ T_E cells undergo apoptosis at the contraction phase (8–15 days) and leave a subpopulation differentiating into T_EM, whereas T_MP cells keep self-renewal and give rise to T_CM, T_EM and T_RM cells over 30 days post-infection

Fig. 4

Effector CD4⁺ and CD8⁺ T cells contribute to infectious immunity. In response to infection, naïve CD8⁺ T cells develop into CD8⁺ CTLs expressing a range of chemokine receptors and effector molecules, whereas naïve CD4⁺ T cells develop into distinct Th1, Th2, Th17, Th22, Tfh, and CTL subsets with indicated phenotypes to exert protective functions. In addition, CD4⁺ T cells indirectly contribute to pathogen clearance by providing help to macrophages, CD8⁺ CTLs and B cell and antibody responses

Fig. 5

Heterogenous populations and differential trajectory of CD8⁺ Tex cells in chronic infection and tumor. Under persistent antigen stimulation, CD8⁺ T cells adopt an exhaustion differentiation trajectory of naïve → T_MP → stem-like Tpex → effector-like transitory → intermediate → terminal Tex cells. Expression of signature markers and effector molecules at each Tex population is indicated. The stem-like Tpex cells are further divided into early precursor and late progenitor stages with discrete phenotype, proliferative status and preferential location. Tex subsets identified from different studies may use different names which are marked in the parentheses. CXCL13 and IL-21 derived from CD4⁺ T cells are critical for differentiation of CXCR5⁺ Tpex cells and CX3CR1⁺ Teff-like transitory Tex cells, respectively. CD8⁺ Tpex cells interplay with cDC1s through XCL1/XCR1 axis

Fig. 6

CD4⁺ T cells support CD8⁺ CTL response in anti-tumor immunity. Effective CD8⁺ CTL priming is a two-step process dependent on CD4⁺ T cell help which is bridged by XCR1⁺ resident cDC1s. CD4⁺ and CD8⁺ T cells are activated separately by different populations of DCs. Through CD40/CD40L signaling, activated CD4⁺ T cells enhance the expression of CD80/CD86 and CD70 on cDC1s, which interact with CD28 and CD27 on CD8⁺ T cells to promote their activation. CD4⁺ T cell-helped cDC1s also secrete high levels of type I interferon, IL-12 and IL-15 to promote CD8⁺ T cell survival and effector function. CD4⁺ T cells can directly promote CD8⁺ CTL response through IL-2 and IL-21. Consequently, CD4⁺ T cell-helped CD8⁺ T cells exhibit enhanced expansion, cytotoxic activity, migratory capacity, and expression of TNFR and key transcription factors, while downregulated IRs

Fig. 7

The anti- and pro-tumor immunity of γδ T cells. γδ T cells in TME play both anti- and pro-tumor activities. γδ T cells recognize phosphoantigens bound by BTN3A1/BTN2A1 heterodimers, as well as recognize glycolipids presented by CD1d. γδ T cells can directly kill tumor cells by expressing cytotoxic factors perforin and granzymes, and apoptotic receptors TRAIL and FasL. IFN-γ produced by γδ T cells enhances MHC I expression on tumor cells and their antigen presentation to CD8⁺ αβ T cells. γδ T cells are able to present antigens to CD4⁺ and CD8⁺ αβ T cells through MHC II and MHC I molecules, respectively. γδ T cells orchestrate the anti-tumor immunity through interacting and activating DCs, NK cells, and B cells. Expression of NKRs and TLRs promote γδ T cells activation and effector function. PD-1-expressing γδ T cells are the main responder to ICB in MHC I-deficient cancers. The pro-tumor activity of γδ T cells relies on both soluble factors and surface receptors by promoting tumor cell growth and angiogenesis, suppressing αβ T cell function, MDCSs induction, and inducing inhibitory functions