T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin-12 and interferon-γ and is inhibited by transforming growth factor-β

A T helper type 1 (Th1)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45RB(high) CD4+ splenic T cells and could be prevented by cotransfer of CD45RB(low) CD4+ T cells. Inhibition of this Th1 response by the CD45RB(low) T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) beta antibody. Interleukin (IL) 4 was not required for either the differentiation of function of protective cells as CD45RB(low) CD4+ cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4+ cells and TGF-beta as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Th1 responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.

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Transforming growth factor-β controls T helper type 1 cell development through regulation of natural killer cell interferon-γ

Nature Immunology ◽

10.1038/ni1197 ◽

2005 ◽

Vol 6 (6) ◽

pp. 600-607 ◽

Cited By ~ 281

Author(s):

Yasmina Laouar ◽

Fayyaz S Sutterwala ◽

Leonid Gorelik ◽

Richard A Flavell

Keyword(s):

Growth Factor ◽

Natural Killer Cell ◽

Natural Killer ◽

Transforming Growth Factor ◽

Killer Cell ◽

Transforming Growth Factor Β ◽

Interferon Γ ◽

T Helper ◽

Helper Type

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T Helper Type 2 Cell Differentiation Occurs in the Presence of Interleukin 12 Receptor β2 Chain Expression and Signaling

Journal of Experimental Medicine ◽

10.1084/jem.191.5.847 ◽

2000 ◽

Vol 191 (5) ◽

pp. 847-858 ◽

Cited By ~ 53

Author(s):

Ryuta Nishikomori ◽

Rolf O. Ehrhardt ◽

Warren Strober

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Th2 Cells ◽

Interleukin 12 ◽

Th1 Cells ◽

T Helper ◽

Ifn Γ ◽

Helper Type

The differentiation of CD4+ T cells into T helper type 1 (Th1) cells is driven by interleukin (IL)-12 through the IL-12 receptor β2 (IL-12Rβ2) chain, whereas differentiation into Th2 cells is driven by IL-4, which downregulates IL-12Rβ2 chain. We reexamined such differentiation using IL-12Rβ2 chain transgenic mice. We found that CD4+ T cells from such mice were able to differentiate into Th2 cells when primed with IL-4 or IL-4 plus IL-12. In the latter case, the presence of IL-4 suppressed interferon (IFN)-γ production 10–100-fold compared with cells cultured in IL-12 alone. Finally, in studies of the ability of IL-12 to convert Th2 cells bearing a competent IL-12R to the Th1 cells, we showed that: (a) T cells bearing the IL-12Rβ2 chain transgene and primed under Th2 conditions could not be converted to Th1 cells by repeated restimulation under Th1 conditions; and (b) established Th2 clones transfected with the IL-12Rβ2 chain construct continued to produce IL-4 when cultured with IL-12. These studies show that IL-4–driven Th2 differentiation can occur in the presence of persistent IL-12 signaling and that IL-4 inhibits IFN-γ production under these circumstances. They also show that established Th2 cells cannot be converted to Th1 cells via IL-12 signaling.

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Interferon γ Derived from CD4+ T Cells Is Sufficient to Mediate T Helper Cell Type 1 Development

Journal of Experimental Medicine ◽

10.1084/jem.188.9.1651 ◽

1998 ◽

Vol 188 (9) ◽

pp. 1651-1656 ◽

Cited By ~ 62

Author(s):

Adil E. Wakil ◽

Zhi-En Wang ◽

James C. Ryan ◽

Deborah J. Fowell ◽

Richard M. Locksley

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Interferon Γ ◽

Receptor Expression ◽

Interleukin 12 ◽

T Helper ◽

Activated T Cells ◽

Ifn Γ

Interferon γ (IFN-γ) has been implicated in T helper type 1 (Th1) cell development through its ability to optimize interleukin 12 (IL-12) production from macrophages and IL-12 receptor expression on activated T cells. Various systems have suggested a role for IFN-γ derived from the innate immune system, particularly natural killer (NK) cells, in mediating Th1 differentiation in vivo. We tested this requirement by reconstituting T cell and IFN-γ doubly deficient mice with wild-type CD4+ T cells and challenging the mice with pathogens that elicited either minimal or robust IL-12 in vivo (Leishmania major or Listeria monocytogenes, respectively). Th1 cells developed under both conditions, and this was unaffected by the presence or absence of IFN-γ in non-T cells. Reconstitution with IFN-γ–deficient CD4+ T cells could not reestablish control over L. major, even in the presence of IFN-γ from the NK compartment. These data demonstrate that activated T cells can maintain responsiveness to IL-12 through elaboration of endogenous IFN-γ without requirement for an exogenous source of this cytokine.

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Faculty Opinions recommendation of Acute stimulation generates Tim-3-expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732439267.793543523 ◽

2018 ◽

Author(s):

Larry Kane

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Effector Function ◽

T Helper ◽

Helper Type

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Mechanism of Transforming Growth Factor β–induced Inhibition of T Helper Type 1 Differentiation

Journal of Experimental Medicine ◽

10.1084/jem.20012076 ◽

2002 ◽

Vol 195 (11) ◽

pp. 1499-1505 ◽

Cited By ~ 326

Author(s):

Leonid Gorelik ◽

Stephanie Constant ◽

Richard A. Flavell

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Inhibitory Effect ◽

Interleukin 12 ◽

T Helper ◽

Retroviral Transduction ◽

Cell Functions ◽

Proliferation And Differentiation ◽

Direct Inhibitory Effect

Regulation by transforming growth factor (TGF)-β plays an important role in immune homeostasis. TGF-β inhibits T cell functions by blocking both proliferation and differentiation. Here we show that TGF-β blocks Th1 differentiation by inhibiting the expression of T-bet, the apparent masterregulator of T helper (Th)1 differentiation. Restoration of T-bet expression through retroviral transduction of T-bet into developing Th1 cells abrogated the inhibitory effect of TGF-β. In addition, we show that, contrary to prior suggestions, downregulation of interleukin 12 receptor β2 chain is not key to the TGF-β–mediated effect. Furthermore, we show that the direct inhibitory effect of TGF-β on T cells is responsible, at least in part, for the inability of BALB/c mice to mount a Leishmania-specific Th1 response and to clear Leishmanial infection.

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