Tailored immune responses: novel effector helper T cell subsets in protective immunity

Abstract

Differentiation of naïve CD4⁺ cells into functionally distinct effector helper T cell subsets, characterised by distinct "cytokine signatures," is a cardinal strategy employed by the mammalian immune system to efficiently deal with the rapidly evolving array of pathogenic microorganisms encountered by the host. Since the T(H)1/T(H)2 paradigm was first described by Mosmann and Coffman, research in the field of helper T cell biology has grown exponentially with seven functionally unique subsets having now been described. In this review, recent insights into the molecular mechanisms that govern differentiation and function of effector helper T cell subsets will be discussed in the context of microbial infections, with a focus on how these different helper T cell subsets orchestrate immune responses tailored to combat the nature of the pathogenic threat encountered.

Figure 1. Currently known T_H cell subsets.

Polarising cytokines encountered during T_H cell differentiation drive the expression of subset-specific transcription factors, which imprint subset-specific transcriptomes in the T_H cell. These transcription factors define the effector function and migratory capability of the T_H cell via regulation of subset-specific cytokines and chemokine receptors.

Figure 2. Novel T_H subsets in inflammation.

(A) T_H17 and T_H22 cells have overlapping functions in the mouse. Via production of the inflammatory mediators IL-17A, IL-17F, GMCSF (T_H17), and IL-22 (T_H22), these T_H subsets mediate protective immunity against extracellular pathogens intimately associated with mucosal barriers. (B) T_H9-cell-derived IL-9 may play an important role in antiparasitic immunity via mediating mast cell activation and mastocytosis, increasing the chemotactic potential of an inflammatory site via regulation of inflammatory chemokine production, and promote basophil and eosinophil function.

Figure 3. Mechanism of action of T_FH cells.

T_FH cells are effector T_H cells that govern the quality and magnitude of an antibody response via regulation of B cell selection, differentiation, proliferation, and class switch recombination. T_FH cells execute these effector functions via expression of various cell surface proteins and cytokines (including IL-21). They are generated during antigen presentation in the T cell areas of secondary lymphoid organs in the presence of IL-21 and IL-6, which is thought to upregulate their master transcription factor Bcl6 (pre-T_FH), after which they migrate to the T∶B border where interaction with cognate B cells regulates a number of processes including promoting survival of recently activated B cells, regulating the fate decision of a B cell down extrafollicular plasmablast or germinal center (GC) B cell differentiation pathways, and induction of class switch recombination in GC B cells. Stable interactions with cognate B cells at this border also consolidate the T_FH cell programme (pre-T_FH to T_FH cell differentiation) with further upregulation of Bcl6 and entry into developing GCs. Within GCs, T_FH cells are crucial for the regulation of affinity maturation, development of memory B cell populations, and high-affinity antibody responses via regulation of long-lived plasma cell differentiation.