The Th1-Th2 paradigm provides a framework for understanding T cell biology and the interplay of innate and adaptive immunity.

This article is a work in progress.

Last review and update: July 29, 2020.

A short summary.

The roles and interactions of Th1, Th2 and Th17 immunity is a fascinating piece of physiological literacy with implications in the treatment of viral infections, allergies and autoimmune disorders. Weaver and colleagues, 2007 (1), produced a quality review on the topic. In the article below, we shared our notes and several curated citation from the review by Weaver and colleagues (1) as well as from other sources.

Th1 and Th2 immunity evolved to enhance clearance of intracellular pathogens and parasitic helminthes, respectively.

Weaver et al., 2007 (1):

Th17 cells appear to have evolved as an arm of the adaptive immune system specialized for enhanced host protection against extracellular bacteria and some fungi, microbes probably not well covered by Th1 or Th2 immunity, that evolved to enhance clearance of intracellular pathogens and parasitic helminthes, respectively.

Th17 cells are the principal pathogenic effectors in several types of autoimmunity previously thought to be Th1-mediated.

Weaver et al., 2007 (1):

The identification of Th17 cells as the principal pathogenic effectors in several types of autoimmunity previously thought to be Th1-mediated promises new approaches for therapies of these disorders, as does identification of IL-25 as a potentially important mediator of dysregulated Th2 responses that cause asthma and other allergic disorders.

Th1-Th2 paradigm.

Weaver et al., 2007 (1):

CD4 T cells play a central role in orchestrating immune responses through their capacity to provide help to other cells of the adaptive or innate immune systems. In early studies of CD4 T cell biology, it became apparent that two classes of CD4 T cells could be defined: those that helped B cells for class switching, or promoted humoral immunity, and those that enhanced macrophage activation, or promoted cell-mediated immunity.

The induction of one type of response, e.g. anti-bacterial/anti-viral Th1, suppresses the induction of the other.

Weaver et al., 2007 (1):

Mosmann & Coffman (5) proposed the T helper type 1 (Th1)-Th2 hypothesis, which postulated that subsets of CD4 T cells produce reciprocal patterns of immunity through their production of distinct profiles of cytokine secretion—either delayed-type hypersensitivity/cell-mediated immunity (Th1) or allergic/humoral immunity (Th2). Furthermore, each subset promotes its own development and inhibits the development of the other subset, also via their secreted cytokines (6, 7), such that the induction of one type of response suppresses the induction of the other (8).
This hypothesis established a new paradigm for understanding immune regulation by CD4 T cells and led to the appreciation that effector CD4 T cells, like class-switched B cells, are functionally heterogeneous.

The Th1-Th2 hypothesis explained the divergence of distinct types of immunity—types 1 and 2, induction of which could determine success or failure of host protection, depending on the type of pathogen.

Weaver et al., 2007 (1):

Th1 cells were defined on the basis of their production of interferon (IFN)-γ, a potent macrophage-activating cytokine important in the clearance of certain intracellular pathogens and a switch factor for induction of IgG2a production by B cells. Th2 cells became defined as producers of IL- 4 and IL-5, which promote IgG1 and IgE class switching and eosinophil recruitment. Th2 cells were later shown also to produce IL-13, which participates in IgE class switching and is important for mucosal activation (mucus hypersecretion and increased contrac- tility). Accordingly, the cytokines produced by Th2 cells also became identified as factors involved in the clearance of helminthes (reviewed in 9). The importance of an appropriate Th1 or Th2 response was demonstrated in early studies that examined host protection to challenge by the obligate intracellular protozoal parasite, Leishmania major, by genetically resistant and susceptible strains (10). Protection of a resistant mouse strain, C57Bl/6, correlated with an appropriate Th1- mediated IFN-γ response, whereas susceptibility of BALB/c mice correlated with an inappropriate Th2-mediated IL-4 response (11). Susceptible BALB/c mice could be protected by transfer of a Th1 cell line specific to an immunodominant L. major antigen, whereas transfer of a Th2 cell line exacerbated disease (12). Thus, the Th1-Th2 hypothesis explained the divergence of distinct types of immunity—types 1 and 2, induction of which could determine success or failure of host protection, depending on the type of pathogen.

Th2 development was proven to depend on IL-4.

Weaver et al., 2007 (1):

Th2 development was soon proven to depend on IL-4, providing the first indication of a positive feedback loop whereby a cytokine produced by effector T cells could induce the differentiation of additional effectors of the same phenotype (13, 14). Thus, Th2 cells may beget Th2 cells, through an IL-4-dependent mechanism.

IFN-γ alone could not induce as robust a Th1 response as that of macrophage-derived factors.

Weaver et al., 2007 (1):

Discovery of the factors that induce Th1 development followed from studies that directly examined the effects of a Th1-associated pathogen, Listeria monocytogenes, on the differentiation of naive CD4 T cells. Murphy and coworkers (15) found that macrophages activated by heat-killed L. monocytogenes induced strongly polarized Th1 responses and that this effect could be blocked by neutralization of IFN-γ, although IFN-γ alone could not induce as robust a Th1 response as that of macrophage-derived factors elicited by heat-killed L. monocytogenes. This implicated an additional factor acting in concert with IFN-γ to induce Th1 differentiation.

IL-12, a cytokine that had been defined as a potent inducer of IFN-γ production by NK cells (16), was soon identified as the Th1-inducing cofactor responsible for Th1 development.

Weaver et al., 2007 (1):

IL-12, a heterodimeric cytokine that had been defined as a potent inducer of IFN-γ production by NK cells (16), was soon identified as the Th1-inducing cofactor responsible for Th1 development (17, 18). This provided a mechanism linking pathogen-driven innate immune activation to a directed adaptive T cell response and introduced a new cytokine pathway involved in coordination of innate and adaptive immune responses. Thus, cytokine signals induced by firstline innate responses could guide the adaptive response to enhance pathogen clearance (19).

Early IL-4 signaling rapidly initiates positive and negative feedback loops that serve to reinforce early commitment to Th2 development while extinguishing Th1 development.

Weaver et al., 2007 (1):

Although Th1 and Th2 cells can themselves provide IFN-γ or IL-4 for the recruitment of Th1 or Th2 differentiation, respectively, investigators have not yet definitively determined which cells initiate effector T cell differentiation in primary versus secondary responses. Plasmacytoid dendritic cells (DCs), NK cells, or NKT cells appear to be involved in early production of type I and II IFNs for induction of Th1 cells, but which cells initiate Th2 development is less clear. Basophils, eosinophils, mast cells, and NKT cells are sources of IL-4 that may be important for Th2 differentiation (35–39), and each of these cell populations may be important for initiating Th2 responses to distinct pathogens or in distinct settings.

The IL-17 cytokine family.

Th17: An effector lineage distinct from Th1 and Th2.

Weaver et al., 2007 (1):

Both type II and type I IFNs, which activate STAT1- induced expression of T-bet and Th1 commitment, strongly inhibited Th17 development in vitro.

Not only the Th1 pathway is nonpermissive to Th17 development, but also its defining cytokine, IFN-γ, actively suppresses Th17 development.

Weaver et al., 2007 (1):

We found that IL-23 failed to induce IL-17 production from Th1-polarized cells, indicating that Th1 cells are not IL-23-responsive. Furthermore, both type II and type I IFNs, which activate STAT1- induced expression of T-bet and Th1 commitment, strongly inhibited Th17 development in vitro. Together, these findings indicated not only that the Th1 pathway is nonpermissive to Th17 development, but also that its defining cytokine, IFN-γ, actively suppresses Th17 development.

IL-17-producing effectors develop via a lineage that is distinct from, and antagonized by, the Th1 and Th2 lineages.

Weaver et al., 2007 (1):

Parallel findings were made for the Th2 lineage; Th2-polarized cells were unresponsive to IL-23, and IL- 4 potently inhibited Th17 development. Indeed, neutralization of IFN-γ and IL-4— whether by blocking antibodies or genetic deficiency—was required to induce appreciable IL-17-producing effectors under the conditions examined. Key signaling components of Th1 and Th2 differentiation—STAT1, T-bet, STAT4, and STAT6—were dispensable for Th17 development. These findings were extended in vivo by Park et al. (92), who showed that Th17 development was unimpaired in immunized mice deficient for IFN-γ or T-bet. Collectively, these studies established that IL-17-producing effectors develop via a lineage that is distinct from, and antagonized by, the Th1 and Th2 lineages.

Collagen-induced arthritis (CIA): aT cell– and antibody-mediated rodent model of autoimmune arthritis is induced by immunization with collagen proteins.

Weaver et al., 2007 (1):

Collagen-induced arthritis (CIA): aT cell– and antibody-mediated rodent model of autoimmune arthritis in which chronic joint inflammation is induced by immunization with collagen proteins; models many aspects of rheumatoid arthritis.

Why mice with targeted deletions of IFN-γ, IFN-γ R, IL-12, or STAT1 (part of the Th-1 response) display exacerbated collagen-induced arthritis (CIA).

Weaver et al., 2007 (1):

These findings offer explanations for a number of the paradoxical effects observed in the development of EAE and CIA in mice with Th1-lineage defects. Given the pathogenic potential of Th17 cells and the suppressive effects of IFN-γ on Th17 development, a mechanism now exists to explain why mice with targeted deletions of IFN-γ, IFN-γ R, IL-12, or STAT1 display exacerbated disease development.

What is “transforming growth factor beta (TGF-beta)”?

Wahl, 1994:

A is often the case with peptide growth factors and cytokines, the original activity discovered and identified as TGF-beta merely represented the tip of the iceberg. Not only does it regulate growth, as evident by its name, but TGF-beta mediates far-ranging biologic processes including inflammation and host defense, in addition to development, tissue repair, and tumorigenesis. Released locally from platelet stores early in an inflammatory response, TGF-beta is then generated by inflammatory cells themselves as part of the cytokine net- work. Initially, in its defensive role, TGF-beta mediates the egress of undifferentiated leukocytes and, subsequently, it facilitates resolution of inflammation and promotes tissue repair (1, 2). But this carefully choreographed series of events, which represents the “good” side of TGF-beta, is dependent upon a critical balance of the growth factor. It is becoming increasingly evident that too much of a good thing can be bad; excess TGF-beta within a lesion has been associated with unresolved inflammation and fibrotic events (1-3).

To be continued.

Selected references:

1. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821-852.

2. Wahl SM. Transforming growth factor beta: the good, the bad, and the ugly. J Exp Med. 1994;180(5):1587-1590.