Lymphocyte proliferation in immune-mediated diseases

Datta, Shrimati; Sarvetnick, Nora

doi:10.1016/j.it.2009.06.002

Cited by 82 publications

(70 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In humans several autoimmune diseases including type 1 diabetes, rheumatoid arthritis and Crohns have been associated with lymphopenia 42,43 . 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 .…”

Section: Discussionmentioning

confidence: 99%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

View full text Add to dashboard Cite

show abstract

“…The presence of alloreactive and autoreactive clones in the T cell repertoire is determined by thymus-dependent pathways, but activation and expansion of naive clonal populations are regulated in peripheral lymphoid organs by Ag encounter, homeostatic mechanisms, and the inhibitory network of Tregs (20,21). In the current study, we showed that the homeostatic cytokine IL-7 directly interferes with an important regulatory checkpoint of autoimmunity and releases T cells from the inhibitory network of Tregs.…”

Section: Discussionmentioning

confidence: 99%

IL-7 Abrogates Suppressive Activity of Human CD4+CD25+FOXP3+ Regulatory T Cells and Allows Expansion of Alloreactive and Autoreactive T Cells

Heninger

Theil

Wilhelm

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

CD4+CD25+FOXP3+ regulatory T cells (Tregs) control the activation and expansion of alloreactive and autoreactive T cell clones. Because uncontrolled activation and expansion of autoreactive T cells occur in an IL-7–rich environment, we explored the possibility that IL-7 may affect the function of Treg. We show that the functional high-affinity IL-7R is expressed on both naive and memory Tregs, and exposure to IL-7 results in STAT-5 phosphorylation. Naive, but not memory, Tregs proliferated greatly and acquired a memory phenotype in the setting of a suppression assay when IL-7 was present. Importantly, the presence of IL-7 abrogated the capacity of Tregs to suppress proliferation of conventional T cells in response to TCR activators, including alloantigens and autoantigens. Removal of IL-7 restored the suppressive function of Tregs. Preblocking of the IL-7R on the Tregs also restored suppressor function, indicating that IL-7 directly affected Treg function. Thus, prolonged periods of homeostatic expansion can temporarily release natural regulatory brakes on T cells, thereby providing an additional mechanism for activating and expanding alloreactive and autoreactive T cells.

show abstract

“…The presence of alloreactive and autoreactive clones in the T cell repertoire is determined by thymus-dependent pathways, but the activation and expansion of naive clonal populations are regulated in the peripheral lymphoid organs by antigen encounter, homeostatic mechanisms, and the inhibitory network of Treg cells [18,19]. However, the interaction between T cell response and Treg proliferation in GD is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Treatment of Graves’ disease with methimazole in children alters the proliferation of Treg cells and CD3+ T lymphocytes

Klatka

Kaszubowska

Grywalska

et al. 2014

Folia Histochem Cytobiol.

View full text Add to dashboard Cite

Almost all cases of hyperthyroidism in children result from Graves' disease (GD). Recent studies have confirmed a significant role of T regulatory cells (Tregs) in the development of autoimmune diseases. However, the interactions between T cell responses and Treg proliferation in GD are still poorly understood. The aim of this study was to assess the proliferation of Treg cells (Tregs) and CD3+ T lymphocytes isolated from 50 children with GD before and after treatment with the thyreostatic drug methimazole (MMI). The proliferation rates, measured by methyl-3H-thymidyne incorporation, of CD3+ cells and Tregs stimulated with mitogen phorbol 12-myristate 13-acetate (PMA) were compared with those of unstimulated cells. The proliferation rates of both PMA-stimulated and unstimulated CD3+ cells prior to treatment with MMI were significantly higher than after treatment. Simultaneously, the proliferation rates of both PMA-stimulated and unstimulated Tregs were significantly lower before MMI treatment. Moreover, we observed higher cell proliferation rates of unstimulated and PMA-stimulated Tregs before the initiation of MMI therapy and after treatment in patients who had no relapse of hyperthyroidism. There was a positive correlation between the CD3+ cells proliferation rate before MMI treatment and fT3, as well as fT4 concentration in peripheral blood. The proliferation rates of CD3+ T cells before and after MMI treatment positively correlated with the TSI index. Thus, children suffering from Graves' disease presented lower Tregs proliferative potential compared with CD3+ T cells. Cocultures of CD3+ T cells and Tregs showed that Tregs were not capable of efficiently inhibiting the proliferation of CD3+ T cells in GD patients. Conclusions. MMI treatment reduced the proliferative activity of CD3+ T cells in pediatric GD patients and increased the proliferation rate of Tregs. We suggest that Treg cells that are partly dysfunctional in GD disease are probably suppressed by CD3+ T cells and that methimazole exerts some immunomodulatory effects.

show abstract

Lymphocyte proliferation in immune-mediated diseases

Cited by 82 publications

References 92 publications

PTPN2 attenuates T-cell lymphopenia-induced proliferation

PTPN2 attenuates T-cell lymphopenia-induced proliferation

IL-7 Abrogates Suppressive Activity of Human CD4+CD25+FOXP3+ Regulatory T Cells and Allows Expansion of Alloreactive and Autoreactive T Cells

Treatment of Graves’ disease with methimazole in children alters the proliferation of Treg cells and CD3+ T lymphocytes

Contact Info

Product

Resources

About