CD4 T Helper Cell Subsets and Related Human Immunological Disorders

Abstract

The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.

Keywords: ILCs; Tfh; Th1; Th17; Th2; Treg; immunological diseases; pathogens.

Figure 1

The development and functions of CD4 T helper (Th) and innate lymphoid cell (ILC) subsets. Naïve CD4 T cells can differentiate into Th1, Th2, Th17, Tfh (follicular T helper), and Treg (T regulatory) subsets upon T cell receptor (TCR) activation in different cytokine milieu. T cells may also become cytotoxic CD4 T cells (CD4-CTLs) that kill their target cells in major histocompatibility complex class II (MHCII)-restricted manner. ILC1, ILC2, and ILC3 subsets are the innate counterparts of Th1, Th2, and Th17 cells and they are involved in type 1, type 2, and type 3 immune responses, respectively. ILC1, ILC2, and ILC3 subsets develop from ILC progenitors (ILCPs), which are distinct from progenitors that give rise to natural killer (NK) cells and lymphoid tissue inducers (LTis).

Figure 2

Crosstalk between ILC2s and Th2 cells during type 2 immune responses. Upon stimulation by helminth products or allergens, epithelial and/or stromal cells may produce inflammatory cytokines including IL-33, IL-25, and TSLP, which are capable of activating ILC2s. By producing type 2 effector cytokines, such as IL-4 and IL-13, ILC2s may promote the migration of dendritic cells (DCs) into draining lymph nodes to induce Th2 cell differentiation. Some ILC2s also express MHCII, which allows them to directly interact with Th2 cells through antigen presentation. Thus, ILC2s could promote the further differentiation of early Th2 cells; on the other hand, Th2 cells may expand ILC2s through IL-2 production. Effector cytokines including IL-4 and IL-13 produced by Th2 cells, may also indirectly induce the expansion of ILC2s through stimulating epithelial cells to produce ILC2-activating inflammatory cytokines such as IL-25 and TSLP.