Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy

Abstract

This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy--a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4⁺ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8⁺ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4⁺ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors.

Keywords: CD4 T cells; CD8 T cells; cancer; chimeric antigen receptor (CAR); immunotherapy.

Figure 1

The structure of chimeric antigen receptor construct. The first, second, and third generation of CAR constructs are shown. The first generation of CAR has only an activation domain; the second generation of CAR has one activation domain and one co-stimulatory domain; and the third generation of CAR has one activation domain and two co-stimulatory domains. The ectodomain consists of antibody-derived antigen binding scFv (single chain variable fragment) with the variable fragment of heavy chain, VH, and the variable fragment of light chain VL, which are connected with a linker. The hinge region connects ScFv with the transmembrane domain. The endodomain consists of the co-stimulatory domains (CD28; CD137 or 4-1BB) and the activating domain: CD3 zeta.

Figure 2

Different CD4⁺ T cell subsets. The different CD4⁺ subsets are generated from the naive T cells by the different cytokines. Each CD4⁺ subset produces a different type of interleukins.

Figure 3

The differentiation of CD4⁺ T naive and Treg cells. The markers of each T cell type are shown during T cell differentiation. The abbreviations: TN, naive T cells; T _CM, central memory T cells; T _EFF, effector T cells; T _EM, effector memory cells; Treg, regulatory T cells.

Figure 4

The differentiation of CD8⁺ T cells and different CD8⁺ subsets. TN, naive T cells; T _SCM, stem cell memory T cells; T _CM, central memory T cells; T _EFF, effector T cells; T _EM, effector memory cells.

Figure 5

Different metabolic pathways of T cells. T naive cells and T memory cells have catabolic metabolism. T effector cells have anabolic metabolism. PI3 Kinase, PI3K; AKT and mTOR are key players of anabolic metabolism of T effector cells.

Figure 6

Different potential approaches to increase the efficacy of CAR-T cell therapy. The inhibition of Treg cells; inhibition of immune checkpoints such as PD-1 and CTLA-4; different T cell subsets, individualized T cell profiling; targeting T cell metabolism; combination of different cytokines and co-stimulatory CAR domains can be used to increase the efficacy of CAR-T cell therapy. Blocking PD-1 or CTLA-4 can increase efficacy of CAR-T therapy. Activation of glycolysis stimulates T_EFF cells, while activation of fatty acid oxidation induces T_EM cells. Different CAR co-stimulatory domain structure can affect T cell memory and effector functions with distinct metabolism (CAR-T cells with CD28 induce effector memory functions and glycolytic metabolism, and CAR-T with 4-1BB induce central memory and oxidative metabolism [46]) that can be applied to improve CAR-T immunotherapy.