Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4

Tivol, Elizabeth; Borriello, Frank; Schweitzer, A.; Lynch, William T.; Bluestone, Jeffrey A.; Sharpe, Arlene H.

doi:10.1016/1074-7613(95)90125-6

Cited by 2,650 publications

(1,836 citation statements)

References 27 publications

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“…However, the increased numbers of CD4 1 FOXP3 1 T cells found in autoimmune inflammatory environments such as EAE or the rheumatoid joint [59][60][61] has been used to support the argument that Treg are expanded in inflammation but are unable to establish control [62]. Although defective CTLA-4 function and an expanded CD4 1 FOXP3 1 population in lupus patients may not be connected, there is a striking parallel found in CTLA-4-deficient mice [1,2]. It was originally noted that there is a marked increase in the number of CD4 1 CD25 1 T cells in mice lacking CTLA-4.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of CTLA-4 in the down-modulation of immune responses is demonstrated in CTLA-4-deficient mice that develop a lethal lymphoproliferative syndrome with features of autoimmunity [1,2]. It is worth noting that by 3-5 wk, CTLA-4 -deficient mice suffer from a severe lupus-like autoimmune syndrome, which is more rapid in onset than other mouse models of systemic lupus erythematosus (SLE) [3].…”

Section: Introductionmentioning

confidence: 99%

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Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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CTLA‐4 is a critical gatekeeper of T‐cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA‐4 in SLE. Our results reveal increased CTLA‐4 expression in FOXP3− responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA‐4 was unable to regulate T‐cell proliferation, lipid microdomain formation and phosphorylation of TCR‐ζ following CD3/CD28 co‐stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co‐stimulation, there was no parallel increase in CTLA‐4 expression, which would normally provide a break on T‐cell proliferation. These defects were associated with exclusion of CTLA‐4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA‐4 dysfunction as a potential cause for abnormal T‐cell activation in patients with SLE, which could be targeted for therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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“…CTLA-4 has a homologous structure to CD28 and binds to the same ligands, CD80/CD86, as CD28, but with much higher affinity. CTLA-4-deficient ( -/-) mice exhibit massive lymphoproliferative disorder and die at around 5 weeks of age [5,6]. It has been suggested that this lymphoproliferative disorder in CTLA-4 -/-mice is induced by polyclonal activation of peripheral T cells and that it is not due to a defect in the elimination of autoreactive T cells in the thymus [7][8][9][10], providing evidence for the in vivo function of CTLA-4 as a negative regulator of T cell responses [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…CTLA-4-deficient ( -/-) mice exhibit massive lymphoproliferative disorder and die at around 5 weeks of age [5,6]. It has been suggested that this lymphoproliferative disorder in CTLA-4 -/-mice is induced by polyclonal activation of peripheral T cells and that it is not due to a defect in the elimination of autoreactive T cells in the thymus [7][8][9][10], providing evidence for the in vivo function of CTLA-4 as a negative regulator of T cell responses [5,6]. However, the conclusion that CTLA-4 does not influence thymic selection was based mainly on the analyses of thymocyte development in TCR-transgenic (Tg) Â CTLA-4-deficient mice [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

et al. 2005

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Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) induces major inhibitory signals for T cell activation. From analyses of TCR‐transgenic (Tg) CTLA‐4‐deficient mice, it has been believed that CTLA‐4 does not affect thymocyte development. To focus upon the in vivo function of CTLA‐4 in thymocyte development from a different aspect, we have established Tg mice expressing either full‐length CTLA‐4 (FL‐Tg) or a mutant CTLA‐4 lacking the cytoplasmic region (truncated, TR‐Tg), and analyzed thymocyte development. TR‐T cells express much higher CTLA‐4 on the cell surface than FL‐T cells, in which most CTLA‐4 was localized in intracellular vesicles. While CTLA‐4–/– mice exhibit lymphoproliferative disease, neither of the Tg mice with CTLA‐4–/– background developed the disorder. Although the development of thymocytes appeared normal in both Tg mice, in vivo depletion of double‐positive thymocytes by injection of anti‐CD3 Ab as well as the elimination of minor lymphocyte‐stimulating antigen‐reactive thymocytes were impaired in FL‐Tg mice but not in TR‐Tg mice. Functionally, cross‐linking of CTLA‐4 on thymocytes from FL‐Tg mice, but not from TR‐Tg mice, inhibited proliferation. These results reveal a potential role of CTLA‐4, through its cytoplasmic domain, in the negative selection of thymocytes and in the prevention of lymphoproliferative disease.

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“…CTLA-4 is structurally similar to CD28 and binds to CD80/86 with higher affinity than to CD28 (8), playing a crucial role in maintaining peripheral tolerance (9)(10)(11). Abatacept is a soluble fusion protein of the extracellular domain of CTLA-4 and the modified Fc portion of human IgG1 that eliminates complement activation (12,13).…”

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confidence: 99%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

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Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4

Cited by 2,650 publications

References 27 publications

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

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