Effector T cells are essential in the immune system by providing the proper response, at the right time and the right place: They fight against an orchestra of pathogenic microorganisms, facilitate B cell antibody production, suppress autoimmunity, mediate CD8+ responses, and modulate and adjust responses accordingly to the persistence of other responses. The traditional paradigm suggests that upon TCR activation, naïve CD4+ T cells differentiate into specific helper T cell (Th) lineages: Th1 or Th2. However, within the last century, additional T cell lineages including Th17, Tregs, and Tfh lineages have also been discovered, analyzed, and characterized. Thus, we will focus our attention on the characteristics of different effector T cell lineages and the more recent lineage, Tfh.
Types of Effector Cells:
T cells can be identified as being naïve, effector, or memory T cells by its wide-ranging phenotypes, functions, and anatomical distribution in the human body. Naïve T cell are the most homogenous population, consisting of primarily CD4+and CD8+ T cells. These T cells are activated by a variety of factors. Specifically, Th1 cells are activated by T-bet, Th2 by GATA-3, Th17 by ROR-γt, and Tregs by Foxp3. Upon antigen activation, these T cells can be further distinguished by their cytokine profiles. Activated CD4+ T helper cells can be subdivided into subpopulations of Th1, Th2, Th17, and Tregs based on their cytokine production.
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Two major T helper subpopulations are Th1 and Th2 cells. Th1 cells primarily secrete IFN-γ, IL-2, TNF-α, and lymphotoxin. Th1 cells augment pro-inflammatory responses, influence B cell production of IgG, and protect against protozoa infiltrations. Th2 cells produce IL-4, IL-5, and IL-13 and stimulate non-inflammatory responses. Particularly, they reinforce B cell production of immunoglobulins. Th1 and Th2 are mutually exclusive – Th1 cells are supported by IFN-γ and IL-12 while Th2 development is dependent on IL-4 and IL-10. Though the cytokine secretion profiles of Th1 and Th2 cells are irrefutable, recent data has show that the cytokine-T cell interaction is much more intricate. It has been shown that IL-10, a cytokine attributed to Th2 cells, is also produced by other subsets such as Th1, Th17, and Tregs. Thus, there’s a controversy as to whether these CD4+ T cells are plastic and respond to a range of cytokines, or if the cytokines instigate the T cells to adopt a Th1 or Th2 phenotype. Therefore, the original paradigm of Th1 and Th2 cells has changed – other lineages and factors are adding to the complexity in understanding effector T cells.
Th17 cells were discovered later than Th1 or Th2 but are imperative responders to infections. Th17 cells produce cytokines such IL-17a, IL-17f and chemokines like CXCL8, CXCL2, and GM-GSF. Collectively, these signals direct the recruitment of macrophages and neutrophils to the infection site and stimulate the bone marrow to produce more T cells. Additionally, Th17 cells collaborate with Tregs, to prevent autoimmune diseases. In particular, Tregs secrete immunosuppressive cytokines such as IL-10, IL-35, and TGF-β to maintain and conserve peripheral tolerance and suppressive autoimmunity. Two subpopulations of Tregs, nTregs and iTregs, prevent autoimmunity by suppressing Th1 and Th2 differentiation once the pathogenic threat is removed. Thus, Tregs are able to prevent any false inflammatory responses.
With advances in research, tools, and technologies, a growing spectrum of Th lineages are being uncovered and characterized by the environmental factors they respond to and the transcription factors they can activate. For example, the new Th lineage, follicular T helper cells (Tfh), responds to IL-6 gradients and influences the transcription factor, Bcl6. Thus, by understanding the mechanisms of old subsets, and the discovery of new subsets, science can uncover some of the potential immunological diseases that are associated with these T cell lineages.
Tfh cells and another lineage?
One of the most recent Th lineages to be discovered is the Tfh lineage. Tfh cells are CD4+ T cells that primarily localizes in the SLO near B cell areas. Tfh are capable of leaving T cell areas and migrate toward the germinal centers due to their concurrent expression of CXCR5, a B cell zone homing cytokine, and downregulation of CXCL7, a T cell zone homing cytokine. This migration process and adjacency to B cells allow Tfh to influence B cell activation, expansion, and differentiation through cytokines such as IL-21 and Bcl6.
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Bcl6 serve as a master regulator and a transcriptional repressor. In particular, it facilitates the germinal center (GC) B cell differentiation by modulating V(D)J recombination genes, repressing certain host signaling pathways, and monitoring cell cycle pathways. However, our current understanding of how and through what mechanism by which Bcl6 controls Tfh differentiation is still limited since Bcl6 can bind to hundreds of genes in B cells. Current research has shown that Bcl6 in CD4+ T cells can modulate microRNA expression. Through this mechanism, Bcl6 antagonizes transcription factors important for other T cell subsets: Th1, Th2, or Th17 and prevent their differentiation. Additionally, Bcl6 inhibits Blimp-1, a key regulator for non-Tfh differentiation. By repressing Blimp-1, Bcl6 limits all other effector cell differentiation. Thus, it is interesting how Bcl6 collaborates with these different differentiation pathways at different intensities. It will be intriguing to unravel the mechanisms for how this intricate balance occurs.
Currently, there is little information about how Bcl6 stimulates Tfh differentiation, although three mechanisms have been proposed: 1) Bcl6 antagonizes non-Tfh differentiation, thus favoring Tfh differentiation; 2) Bcl6 suppresses Blimp-1, thus indirectly favoring Tfh states, and 3) Bcl6 modulate a large number of microRNAs that directly control Tfh cell fates, thus increasing likelihood of Tfh differentiation. Bcl6 may trigger Tfh differentiation by one or a combination of these mechanisms; or alternatively, Bcl6 may act through a yet unidentified pathway. However, research has shown that Bcl6 plays an intricate role in generating Tfh cells from CD4+ T cells. After activation of Tfh cells, these cells migrate toward the germinal centers and prime B cells to differentiate into plasma or memory B cells. This interaction with B cells sustains Bcl6 expression and generates a second wave of Bcl6 induction of Tfh cellular division. Therefore, by deciphering the cellular and molecular requirements of Tfh cell differentiation and function will help determine important molecules that could be targeted for autoimmune diseases that are associated with Tfh malfunctions.
The immune response is in part mediated by T cell responses divided into three components: 1) priming of naïve T cells, 2) activating effectors, and 3) preserving long-term memory T cells. For proper and effective immune response requires the activation of T cells by APCs in the SLOs and migration of responding T cells to the site of infection. This efficacy of T cell activation depends on antigenic peptide concentration gradients and affinity of TCR toward pMHC complexes – facilitated by inflammatory stimuli, costimulatory molecules, and cytokine productions. Under different modularity stimulation, these naïve CD4+ T cells can differentiate into 5 major Th subpopulations: Th1, Th2, Th17, Tregs, and Tfh cells.
However, like a double-edged sword, absence of inflammatory stimuli induces insufficient activation of APCs resulting in anergy and apoptosis amongst T cells instead of activation and promotion of immune responses. This intricate balance of homeostasis serves as a mechanism to stimulate immune responses when needed and preserving self- tolerance toward self-antigens. The circulation of T lymphocytes serves as important modulators of the immune system and the immune response.