The immune system encompasses several cell types with distinct functions and mechanisms to recognize and eradicate foreign and abnormal cells. While the innate immune response involves non-specific and rapid attacks toward pathogens, the adaptive immune system exhibits a more targeted approach. T cells are crucial members of the adaptive immune system. Many other immune cell types, mainly dendritic cells (DC) and macrophages, present pathogen- or tumor-specific antigens to T cells. Subsequently. T cells become activated and use the presented antigens as cues to target pathogens or cancer cells.

Overview of CD4 and CD8 T Cells

CD4 and CD8 T cells are two types of T lymphocytes harboring distinct and complementary roles in the adaptive immune system. They are derived from hematopoietic stem cells in the bone marrow, while their maturation occurs in the thymus. Maturation involves the differentiation of these cells into either CD4 helper T cells or CD8 cytotoxic T cells, characterized by distinct surface markers.¹

Role of CD4 T Cells

Also known as helper T cells, CD4 cells recognize antigens and secrete cytokines that activate CD8 T cells, B cells and macrophages to cultivate a multifaceted adaptive immune response.¹

Function of CD8 T Cells

When talking about CD8 T cells, we need to mention two types: cytotoxic and memory CD8 T cells.

Cytotoxic CD8 T cells launch direct attacks on pathogens upon antigen presentation. They exert their cytotoxic effects by forming immunological synapses with their target cells, releasing enzymes and small molecules to trigger apoptotic pathways. They may also produce cytokines, such as IFN-γ and TNF-α.²

On the other hand, memory CD8 T cells provide long-term immunity against pathogens with previously registered antigens. After the initial infection, a group of active CD8 T cells differentiate into memory cells, acquiring longevity and the ability to respond swiftly to future infections. Some circulate throughout the body for constant surveillance, while others become tissue-resident.³

Key Differences Between CD4 and CD8 T Cells

CD4 and CD8 T cells have indirect and direct effects. CD8 T cells act as precise killers of infected or cancerous cells, while CD4 cells coordinate other immune cell types to amplify immune responses.¹ Furthermore, their activation mechanism differs by the antigens presented, as discussed in the next section.

Activation of CD4 and CD8 T Cells

Pathogenic and tumorigenic antigens are represented to T cells as human leukocyte antigens (HLAs) belonging to one of the two major histocompatibility complex (MHC) classes. This process is a prerequisite for T-cell activation. CD8 and CD4 classes recognize MHC class I and class II antigens, respectively. Each T cell type requires additional signals for complete activation.¹

Requirements for CD4 Activation

CD4 T cell activation firstly requires MHC class II molecules presented by antigen-presenting cells (APCs), such as DCs and macrophages. Furthermore, APCs send co-stimulatory signals, such as CD80 and CD86, which bind the surface biomarker CD28 on the CD4 T cell surface. Finally, APCs secrete activating cytokines, such as interleukin-2 (IL-2), that induce CD4 T cell differentiation into specific helper subsets. Without co-stimulation and cytokines, CD4 T cells remain anergic and inactive despite recognizing MHC class II molecules.⁴

Process of CD8 T Cell Activation

The activation of CD8 T cells is similar to that of CD4 T cells, requiring MHC class I molecules and co-stimulation and activating cytokines secreted by APCs and CD4 T helper cells. This three-part activation promotes the proliferation and differentiation of T cells into cytotoxic CD8 T cells.⁵

Role of CD4 in Immunology

CD4 T cells have robust control over the adaptive immune system, as they can differentiate into many subsets to amplify, suppress and prolong immune responses. For example, Th1 and Th2 cells defend the host against pathogenic invasion, while Th17 cells drive inflammation. Thus, they establish a balance, eliminating abnormal cells without the immune system turning on the self-cells.⁶

Regulatory T Cells in the CD4 Lineage

Regulatory T cells (Tregs) are a specialized CD4 T cell subset that maintains homeostasis by suppressing excessive or misdirected immune responses. By secreting inhibitory cytokines, such as IL-10 and TGF-β and modulating CD8 T cell and DC activity, Tregs prevent chronic inflammation and autoimmunity. Their primary function is to assist the immune response in distinguishing between self and non-self-antigens. On the other hand, their persistent activity drives immunosuppression in cancer, allowing tumors to escape immune responses.⁷

CD8 T Cell Differentiation and Development

Naïve T cells undergo a maturation process that differentiates them into effector and memory CD8 T cells, which display distinct functional properties.

Stages of CD8 T Cell Differentiation

Naïve T cells circulate through the lymphatic system and are primed upon encountering signals, such as MHC class antigens, co-stimulatory molecules and cytokines. They subsequently differentiate into cytotoxic (effector) T cells or precursors of memory T cells. Effector T cells undergo apoptosis upon complete antigen clearance after acute infections, while the memory precursors differentiate into long-lived memory T cells after antigen clearance.³

Due to persistent stimulation, another group of CD8 T cells differentiates into exhausted T cells. T-cell exhaustion, characterized by the upregulation of inhibitory receptors, typically occurs in chronic inflammation and many cancer subtypes.⁸

Impact of Cell Differentiation on Immune Responses

T cell differentiation is an intricate process that coordinates, optimizes and regulates adaptive immune responses. Differentiation into effector and memory subsets establishes a balance between cytotoxicity and long-term recall capacity. Effector CD8 T cells exhibit rapid and highly cytotoxic effects on their target pathogens, typically dying after pathogen clearance. Memory CD8 T cells gain long-term survival and recall capabilities that streamline and accelerate adaptive immune responses upon reinfection. Their mechanism of action partly explains why we experience subsequent infections much more mildly than the first infection.⁹

References

1. Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther 2023;8(1):235.
2. Weigelin B, Friedl P. T cell-mediated additive cytotoxicity–death by multiple bullets. Trends Cancer 2022;8(12):980-987.
3. Giles JR, Globig A-M, Kaech SM, Wherry EJ. CD8+ T cells in the cancer-immunity cycle. Immunity 2023;56(10):2231-2253.
4. Xie L, Fang J, Yu J, Zhang W, He Z, Ye L, et al. The role of CD4+ T cells in tumor and chronic viral immune responses. MedComm 2023;4(5):e390.
5. Sarawar SR, Shen J, Dias P. Insights into CD8 T cell activation and exhaustion from a mouse gammaherpesvirus model. Viral Immunol 2020;33(3):215-224.
6. Zhu X, Zhu J. CD4 T helper cell subsets and related human immunological disorders. Int J Mol Sci 2020;21(21):8011.
7. Plitas G, Rudensky AY. Regulatory T cells in cancer. Annu Rev Cancer Biol 2020;4(1):459-477.
8. Baessler A, Vignali DA. T cell exhaustion. Annu Rev Immunol 2024;42(1):179-206.
9. Philip M, Schietinger A. CD8+ T cell differentiation and dysfunction in cancer. Nat Rev Immunol 2022;22(4):209-223.
10. Mittelbrunn M, Kroemer G. Hallmarks of T cell aging. Nat Immunol 2021;22(6):687-698.
11. Savino W, Durães J, Maldonado-Galdeano C, Perdigon G, Mendes-da-Cruz DA, Cuervo P. Thymus, undernutrition, and infection: Approaching cellular and molecular interactions. Front Nutr 2022;9:948488.
12. Franco F, Jaccard A, Romero P, Yu Y-R, Ho P-C. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2020;2(10):1001-1012.
13. Ron R, Martínez-Sanz J, Herrera S, Ramos-Ruperto L, Díez-Vidal A, Sainz T, et al. CD4/CD8 ratio and CD8+ T-cell count as prognostic markers for non-AIDS mortality in people living with HIV. A systematic review and meta-analysis. Front Immunol 2024;15:1343124.
14. Schiweck C, Edwin Thanarajah S, Aichholzer M, Matura S, Reif A, Vrieze E, et al. Regulation of CD4+ and CD8+ T cell biology by short-chain fatty acids and its relevance for autoimmune pathology. Int J Mol Sci 2022;23(15):8272.
15. Minato N, Hattori M, Hamazaki Y. Physiology and pathology of T-cell aging. Int Immunol 2020;32(4):223-231.
16. Ron R, Moreno E, Martínez-Sanz J, Brañas F, Sainz T, Moreno S, et al. CD4/CD8 ratio during human immunodeficiency virus treatment: time for routine monitoring? Clin Infect Dis 2023;76(9):1688-1696.
17. Kuo F-C, Chen C-Y, Lin N-C, Liu C, Hsia C-Y, Loong C-C. Optimizing the safe washout period for liver transplantation following immune checkpoint inhibitors with atezolizumab, nivolumab, or pembrolizumab. Transplant Proc: Elsevier; 2023:878-883.
18. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J 2021;11(4):69.