Suppressing autoimmunity by TGF-β: not just through Treg cells

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Transforming growth factor-β (TGF-β) is a pleiotropic factor. It regulates many aspects of T-cell biology including thymocyte development, T cell differentiation and effector T cell function.1 Previous work has shown that the loss of TGF-β signaling in the T-cell lineage leads to severe lymphoproliferative autoimmunity.2,3 Until now, it has been unclear to what extent the autoimmunity observed in those mice is driven by TGF–unresponsive conventional T cells, as TGF- is also crucial for the maintenance and function of regulatory T cells (Treg). A recent study published in Nature Immunology revealed a novel role of TGF-β signaling in non-regulatory naive T cells. It was found that TGF-β controls lymphopenia-driven T-cell proliferation in neonatal mice, thereby preventing the development of autoimmunity.4

Zhang and Bevan made this discovery by comparing two animal models in which type II TGF-β receptor (TGF-βRII) was ablated in T cells at different developmental stages. In the previous study, researchers specifically deleted TGF-βRII using Cre recombinase driven by the promoter of CD4 (Tgfbr2f/f CD4-Cre). In this model system, TGF-βRII is deleted in T cells by the time they emerge from the thymus. As a result, these mice show severe autoimmunity and early mortality (3–5 weeks). The autoimmune phenotype observed in these mice cannot be rescued by transferring wild-type Treg cells or by reconstituting them with mixed bone marrow from wild-type and Tgfbr2f/f CD4-Cre mice.2,3 Together, these findings show that the onset of autoimmunity in the Tgfbr2f/f CD4-Cre model is at least partially due to the self-reactivity of TGF-β unresponsive conventional T cells. Zhang and Bevan studied a different TGF-βRII conditional deletion model, in which the expression of Cre is driven by the distal promoter of the kinase Lck (Tgfbr2f/f dLck-Cre). In this model, the T cell-specific deletion of TGF-βRII begins in mature T cells and is much slower. Although TGF-βRII is almost completely deleted in T cells in adult mice (7–9 weeks), the expression of TGF-βRII is unaffected in neonates (day 4). The delayed deletion of TGF-βRII led to a different phenotype: Tgfbr2f/f dLck-Cre showed no signs of autoimmune lesions and survived for up to a year.3,4

Using this model, Zhang and Bevan examined why the expression of TGF-βRII on T cells during neonatal development protects the host from autoimmunity later in life. In neonatal mice, the lymphopenic environment allows naive T cells to undergo proliferation driven by weak engagement of the T-cell receptor (TCR) with self ligands and homeostatic cytokines interleukin 7 (IL-7) and IL-15.5 Zhang and Bevan found that TGF-β signaling in naive T cells was essential to restrain this lymphopenia-driven proliferation in neonatal animals. TGF-βRII-deficient naive T cells (from Tgfbr2f/f dLck-Cre mice) proliferated rapidly upon transfer to Rag1−/ or sublethally irradiated wild-type hosts, demonstrating the critical role of TGF-β in regulating homeostatic proliferation in both chronic and acute lymphopenic conditions, respectively. The lack of TGF-β signaling also resulted in an effector phenotype characterized by the increased expression of KLRG1, granzyme B and interferon-γ. The hyperproliferative effector phenotype of TGF-βRII-deficient T cells in Rag1−/ recipients was associated with autoimmunity, as demonstrated by T-cell organ infiltration and weight loss.

The enhanced proliferative capacity of TGF-β-unresponsive T cells does not appear to be caused by commensal bacteria. Commensal flora generates antigens and inflammatory signals, which contribute to rapid T-cell expansion and autoimmunity in the host.6 Loss of commensal bacteria upon antibiotic treatment significantly inhibits the lymphopenia-driven proliferation of wild-type T cells; but fails to control the hyperproliferation of TGF-βRII-deficient T cells. Pro-inflammatory cytokines, such as interferon-γ, IL-6, tumor-necrosis factor, IL-1β and IL-18, did not enhance the proliferation of TGF-β-unresponsive T cells, and interferon-α and IL-12 even reduced the proliferative advantage of TGF-βRII-deficient T cells over wild-type T cells. These results suggest that TGF-β signaling prevents T-cell proliferation induced by weak TCR signals, but does not affect proliferation induced by foreign antigens or pro-inflammatory cytokines.

The most important finding of this study is related to the role of TGF-β signaling in controlling the T-cell response to tonic ‘tickling’.1 During thymocyte development, negative selection deletes T cells with high affinity to self-antigens. Meanwhile, the mature T cells leaving the thymus retain a low affinity to self-ligands. The engagement of TCR by self-ligands in the periphery maintains the viability of naive T cells; however, under certain conditions, unwanted responses and expansion triggered by self-antigens may cause autoimmune disease. Zhang and Bevan showed that TGF-β signaling strongly inhibited T-cell responses to low affinity ligands. When stimulated with a low concentration (1 ng/ml) of T4 ligand (a weak agonist peptide), OT-I T cells proliferated slowly in the presence of TGF-β1, and neutralization of TGF-β greatly enhanced the proliferation rate of these cells. In contrast, OT-I T cells showed comparable proliferation in the presence or absence of TGF-β signaling when stimulated with a high concentration of a strong agonist (N4). The preferential inhibition of naive T-cell responses against low affinity ligands by TGF-β may be a crucial protective mechanism against autoimmunity (Figure 1).

Figure 1
figure1

TGF-β signaling in naive T cells inhibits T-cell responses against low affinity ligands, but not high affinity antigens. When T cells are stimulated with high-affinity antigens (foreign antigens), TGF-β signaling has limited effect on T-cell proliferation (upper panel). In contrast, TGF-β signaling controls the proliferative capacity of T cells upon encounter of low affinity (self-) ligands (lower right panel). TGF-β-unresponsive T cells retain the ability to proliferate robustly in response to low affinity antigens (lower left panel). In neonates and in other lymphopenic conditions, low affinity antigens—such as self antigens—drive the fast homeostatic proliferation of T cells. TGF-β-unresponsive T cells expand excessively, resulting in lymphoproliferative autoimmunity. APC, antigen-presenting cell; TGF-β, transforming growth factor-β.

Despite these findings, this study still may not fully explain the severe autoimmune phenotype observed in the Tgfbr2f/f CD4-Cre model. First, the extent to which the loss of Treg cells in the periphery contributes to the onset of autoimmunity remains unresolved. Unfortunately, TGF-βRII is not deleted in most peripheral Treg cells in the Tgfbr2f/f dLck-Cre model. Although the transfer experiments suggest that factors other than Treg cells caused the autoimmunity observed in the Tgfbr2f/f CD4-Cre model, it is possible that the loss of Treg cells enhances the severity of the disease. Second, because CD4-Cre is expressed before thymic negative selection, the loss of TGF-β signaling may alter the T-cell repertoire. Finally, it should also be noted that the development of NKT cells is abrogated in Tgfbr2f/f CD4-Cre mice.7 Whether this population plays a role in preventing autoimmunity, however, remains unknown.

In summary, Zhang and Bevan's work demonstrates an inhibitory role for TGF-β signaling in naive T cells during homeostatic proliferation in lymphopenic conditions. Moreover, the dampening effect of TGF-β signaling on T-cell activation in response to weak but not strong TCR stimuli provides valuable insight to understand thymocyte development, T cell maintenance and peripheral tolerance.

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Acknowledgements

We would like to thank Dr Claire Gordy for her thoughtful reading of this manuscript. The work in the authors' laboratory is supported by NIH grants AI73947, AI074754 and AI074944.

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