Regulation of human helper T cell subset differentiation by cytokines

doi:10.1016/j.coi.2015.03.007

Current Opinion in Immunology

Volume 34, June 2015, Pages 130-136

https://doi.org/10.1016/j.coi.2015.03.007 Get rights and content

Highlights

•
Development of Th1, Th2, Th9, and Th22 is largely similar between mice and humans.
•
TGF-β and STAT3 signals promote Th17 differentiation in both species.
•
Some differences exist in the development of induced Tregs, Th17, and Tfh cells.
•
Human Th differentiation is largely regulated by IL-12, IL-23, and TGF-β.

Since the discovery of Th1 and Th2 cells in the late 1980s, the family of effector CD4⁺ helper T (Th) cell subsets has expanded. The differentiation of naïve CD4⁺ T cells is largely determined when they interact with dendritic cells (DCs) in lymphoid organs, and cytokines play a major role in the regulation of Th differentiation in the early stages. Recent studies show that the developmental mechanism of certain Th subsets is not fully shared between mice and humans. Here we will review recent discoveries on the roles of cytokines in the regulation of Th differentiation in humans, and discuss the differences between mice and humans in the developmental mechanisms of several Th subsets, including Th17 cells and T follicular helper (Tfh) cells. We propose that the differentiation of human Th subsets is largely regulated by the three cytokines, IL-12, IL-23, and TGF-β.

Introduction

The family of Th subsets has expanded during the past two decades, and currently includes regulatory T cells (Treg), Th17, Tfh, Th9, and Th22 cells. These subsets are largely defined by the cytokines that each subset expresses, except FoxP3⁺ thymus-derived Tregs and T follicular helper (Tfh) cells. Thymus-derived Tregs are defined by the expression of the transcription factor FoxP3 and their suppressive functions. Tfh cells are often defined by the combination of markers (such as CXCR5, ICOS, PD-1, and Bcl-6) and their follicular localization in vivo, although they function by secreting IL-21 and IL-4 (and IL-10 in some cases) [1].

Studies with in vivo mouse models have significantly contributed to understand the developmental mechanism of each Th subsets. However, significant differences have been introduced in the immune system of humans and mice during more than 60 million years of independent evolution, and conclusions demonstrated in mouse studies are sometimes not fully translated to humans [2]. In the context of Th differentiation, it is becoming clear that the developmental mechanism is not fully shared between mice and humans in certain subsets. In this review, we will summarize the current knowledge on the cytokine conditions promoting the development of each Th subset in humans. We classify the Th subsets into two groups according to the similarities in the developmental mechanism between mice and humans: one with large similarities (Th1, Th2, Th9, and Th22) and the other with some differences (induced Treg, Th17, and Tfh). Then we will discuss how cytokines regulate Th differentiation programs in humans.

Section snippets

Th1

IL-12 was discovered in the early 1990s to play the major role for the generation of Th1 cells in both mice and humans [3, 4]. In 1995, STAT4 was identified as the major transcription factor mediating the IL-12 signals, and in 2000, the transcription factor T-bet was discovered to be essential for Th1 development [5]. IFN-γ also contributes to the expression of IFN-γ and T-bet via STAT1 activation [5]. These major pathways associated with the generation of Th1 cells are largely shared between

Induced Treg

While mouse naïve CD4⁺ T cells primed in the presence of IL-2 and TGF-β express high levels of Foxp3, and acquire the capacity to suppress T cell response (termed induced Tregs), human naïve CD4⁺ T cells primed in the same condition do not suppress T cell response despite high expression of Foxp3 [26]. While there is evidence that the addition of retinoic acid or rapamycin to the combination of IL-2 and TGF-β renders human naive CD4⁺ T cells to become FoxP3⁺ suppressors [27, 28], their

Regulation of the differentiation of human Th subsets

We propose that the development of distinct Th subsets in humans is largely regulated by the three cytokines: IL-12, IL-23, and TGF-β. In this context, the differentiation of Th subsets can be viewed as vectors starting from the origin in a three dimensional model (Figure 1). The three cytokines IL-12, IL-23, and TGF-β define the three axes (herein defined as X, Y, Z axis respectively). First, human Th subsets can be largely split into two groups according to the role of TGF-β in their

Conclusions

Some differences have been discovered in the regulation of Th differentiation between mice and humans. There is little doubt that it will be increasingly important to analyze human samples (blood, tissues, urine, body fluids, etc.) and assess whether the findings in mouse models can be translated to humans. Nonetheless, many mechanisms in Th differentiation are remarkably shared between mice and humans, and thus mouse studies will continue to provide important templates to test the pathways in

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

Supported by the US National Institutes of Health (U19-AI057234, U19-AI082715 and U19-AI089987), the Alliance for Lupus Research, Lupus Research Institute, and the Baylor Health Care System.

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Regulation of human helper T cell subset differentiation by cytokines

Highlights

Introduction

Section snippets

Th1

Induced Treg

Regulation of the differentiation of human Th subsets

Conclusions

References and recommended reading

Acknowledgements

Prog Growth Factor Res

Semin Immunol

Trends Immunol

Nat Immunol

Blood

Am J Transplant

Arthritis Rheum

Nat Immunol

Immunity

J Immunol

Immunity

Annu Rev Immunol

Curr Opin Immunol

Blood

Immunity

Science

J Exp Med

J Exp Med

Nat Immunol

Immunity

Pathophysiology of T follicular helper cells in humans and mice

Nat Immunol

Of mice and not men: differences between mouse and human immunology

J Immunol

Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages

Science

Molecular mechanisms regulating Th1 immune responses

Annu Rev Immunol

The lineage decisions of helper T cells

Nat Rev Immunol

How are T(H)2-type immune responses initiated and amplified?

Nat Rev Immunol

Cytokine coexpression during human Th1/Th2 cell differentiation: direct evidence for coordinated expression of Th2 cytokines

J Immunol

Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility

Nat Immunol

A brief history of IL-9

J Immunol

IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma

J Immunol

Human CD4 memory T cells can become CD4+IL-9+ T cells

PLoS ONE

TGF-beta induces IL-9 production from human Th17 cells

J Immunol

Development of TH1 CD4⁺ T cells through IL-12 produced by Listeria-induced macrophages

IL-9 production of naive CD4⁺ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma

Human CD4 memory T cells can become CD4⁺IL-9⁺ T cells