CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity

Calzascia, Thomas; Pellegrini, Marc; Lin, Albert; Garza, Kristine M.; Elford, Alisha R.; Shahinian, Arda; Ohashi, Pamela S.; Mak, Tak W.

doi:10.1073/pnas.0712135105

Cited by 114 publications

(109 citation statements)

References 46 publications

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“…Increased serum IL-7 levels also were described in patients with different autoimmune diseases (15,16,36). Of interest, studies on rheumatoid arthritis and juvenile idiopathic arthritis indicated that augmented IL-7 counteracts the suppressive properties of CD4 + CD25 + CD127 low FOXP3 + regulatory T cells (Tregs) (37)(38)(39).…”

Section: Discussionmentioning

confidence: 98%

“…As a growth factor, IL-7 is involved in the maintenance of naive and memory CD4 + and CD8 + T cells (12)(13)(14). Of note, the level of circulating IL-7 is enhanced in response to lymphopenia in a variety of autoimmune disorders and as a result of chemotherapy and irradiation-based conditioning regimens prior to HSCT (15)(16)(17)(18). In the context of HSCT, the elevated IL-7 serum concentrations were associated with the occurrence and grade of acute GvHD (19)(20)(21).…”

Section: Ouble-negative (Dn) T Cells Are Defined By the Expressionmentioning

confidence: 99%

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IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

Allgäuer

Schreiner

Ferrazzi

et al. 2015

The Journal of Immunology

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Recently, a novel subset of TCRαβ+ CD4− CD8− double-negative (DN) T cells was described to suppress immune responses in both mice and humans. Moreover, in murine models, infusion and/or activation of DN T cells specifically suppressed alloreactive T cells and prevented the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. We demonstrated that human DN T cells, like their murine counterparts, are highly potent suppressor cells of both CD4+ and CD8+ T cell responses. After hematopoietic stem cell transplantation and other lymphopenic conditions, IL-7 plays an important role in the reconstitution, survival, and homeostasis of the T cell compartment. Because IL-7 was shown to interfere with T cell functionality, we asked whether IL-7 affects the functionality of human DN T cells. Intriguingly, IL-7 diminished the suppressive activity of DN T cells toward allogeneic CD4+ effector T cells. Of interest, our studies revealed that IL-7 activates the Akt/mechanistic target of rapamycin (mTOR) pathway in human DN T cells. Importantly, selective inhibition of the protein kinases Akt or mTOR reversed the IL-7 effect, thereby restoring the functionality of DN T cells, whereas inhibition of other central T cell signaling pathways did not. Further analyses suggest that the IL-7/Akt/mTOR signaling cascade downregulates anergy-associated genes and upregulates activation- and proliferation-associated factors that may be crucial for DN T cell functionality. These findings indicate that IL-7 and Akt/mTOR signaling are critical factors for the suppressive capacity of DN T cells. Targeting of these pathways by pharmacological agents may restore and/or enhance DN T cell functionality in graft-versus-host disease.

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Section: Discussionmentioning

confidence: 98%

Section: Ouble-negative (Dn) T Cells Are Defined By the Expressionmentioning

confidence: 99%

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

Allgäuer

Schreiner

Ferrazzi

et al. 2015

The Journal of Immunology

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“…Moreover, mild lymphopenia and compensatory IL-21-dependent homoeostatic proliferation in nonobese diabetic mice that are prone to the development of autoimmunity have been reported to promote type 1 diabetes 44,45 . Similarly, deregulated regulatory T-cell expansion in lymphopenic nonobese diabetic hosts contributes to the development of type 1 diabetes 46 , whereas IL-7-mediated T-cell LIP in lupus or type 1 diabetes predisposed mice enhances their progression to disease 47,48 . In this study we have established for the first time the potential for excessive naive T-cell responses to peptide-MHC in the context of acute lymphopenia to alter the TCR repertoire and contribute to the development of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

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When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8 þ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigenexperienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptordependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

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“…Although this connection bears great therapeutic potential, it also carries undeniable risks. Just as IL-7 treatment for chronic viral infections bears the risk for developing autoimmune diseases by thwarting immune regulation (8)(9)(10), blockade of the IL-7R might increase the susceptibility for certain infections or even cancer in humans. Therefore, the degree to which IL-7Rα actually induces immunosuppression, if at all, needs to be carefully investigated in the future.…”

Section: Pd-1 Pathway Largely Abrogates the Protective Effect Of Ilmentioning

confidence: 99%

“…In both cases, therapeutic administration of recombinant IL-7 enhanced the antigen-specific T-cell responses by amplifying survival and effector mechanisms and counteracting several inhibitory pathways, such as PD-1 (7,8). However, IL-7 has the unfortunate ability to promote the emergence of autoreactive T cells, and thus can be associated with the development of autoimmune diseases (9,10). The importance of IL-7 in the development of autoimmune disorders is further underlined by observations from genome-wide association studies that identified genetic variations of the IL-7Rα chain as risk factors for the development of T1D and multiple sclerosis (11,12).…”

mentioning

confidence: 99%