T-cell subsets in autoimmunity

doi:10.1016/0952-7915(92)90053-H

Current Opinion in Immunology

Volume 4, Issue 6, December 1992, Pages 728-732

https://doi.org/10.1016/0952-7915(92)90053-H Get rights and content

Abstract

The demonstration that functionally different T-cell subsets can be defined by the isoforms of the leukocyte-common antigen, CD45, that they express, has prompted studies on the roles of these subsets in autoimmunity. The results have led to the identification of a particular subset of CD4⁺ T cells that have the ability to inhibit autoimmune disease. Further, it has been shown that diabetes in the B-B rat can be transferred by in vitro activation of T cells by Staphylococcal enterotoxin suggesting that superantigens may play a role in the pathogenesis of this disease. However, in this system too, it appears that a subset of T cells can inhibit the induction of autoaggressive cells. In other experimental autoimmune diseases there is evidence that CD8⁺ T cells can be protective and that these cells may mediate this protection by the synthesis of transforming growth factor-β.

References (41)

P. Scott
Host and Parasite Factors Regulating the Development of CD4⁺ T-cell Subsets in Experimental Cutaneous Leishmaniasis
Res Immunol
(1991)
R.M. Siegel et al.
Mechanisms of Autoimmunity in the Context of T-cell Toler ance: Insights from Natural and Transgenic Animal Model Systems
Immunol Rev
(1990)
D. Mason
Subsets of CD4⁺ T Cells Defined by their Expression of Different Isoforms of the Leukocyte-common Antigen, CD45
Biochem Soc Transactions
(1992)
T. Suzuki et al.
Diabetogenic Effects of Lymphocyte Transfusion on the NOD or NOD Nude Mouse
I.L. Campbell et al.
Essential Role for Interferon-gamma and Interleukin-6 in Autoimmune Insulin-dependent Diabetes in NOD/Wehi Mice
J Clin Invest
(1991)
F. Powrie et al.
OX-22high CD4⁺ T Cells Induce Wasting Disease with Multiple Organ Pathology: Prevention by the OX-22^low Subset
J Exp Med
(1990)
D. Fowell et al.
Subsets of CD4⁺ T Cells and their Roles in the Induction and Prevention of Autoimmunity
Immunol Rev
(1991)
R.M. Locksley et al.
Induction of Th1 and Th2 CD4⁺ Subsets during Murine Leishmania Major Infection
Res Immunol
(1991)
R. Chatelain et al.
IL-4 Induces a Th2 Response in Leisbmania Major-infected Mice
J Immunol
(1992)
L. Cairns et al.
Mice Naturally Tolerant to C5 have T Cells that Suppress the Response to this Antigen
Eur J Immunol
(1986)

O. Taguchi et al.

Self Tolerance and Localized Immunity. Mouse Models of Autoimmune Disease that Suggest Tissue-specific Suppressor T Cells are Involved in Self Tolerance

J Exp Med

(1987)

M. Itoh et al.

Suppression of Efferent Limb of Testicular Autoimmune Response by a Regulatory CD4⁺ T Cell Line in Mice

Clin Exp Immunol

(1992)

K.E. Ellerman et al.

Staphylococcal Enterotoxin-activated Spleen Cells Passively Transfer Diabetes in BB/Wor Rat

Diabetes

(1992)

S. Romagnani

Human Thl and Th2: Doubt No More

Immunol Today

(1991)

G.-F. Del Prete et al.

Purified Protein Derivative of Mycobacterium Tuberculosis and Excretory-Secretory Antigen(s) of Toxocara Canis Expand In Vitro Human T Cells with Stable and Opposite (Type 1 T Helper or Type 2 T Helper) Profile of Cytokine Production

J Clin Invest

(1991)

T.R. Mosmann et al.

Th1 and Th2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional Properties

Ann Rev Immunol

(1989)

J. Kampinga et al.

Postthymic T Cell Development in Rats: an Update

Biocbem Soc Transactions

(1992)

A.N. Akbar et al.

Human CD4⁺CD45RO⁺ and CD4⁺ CD45RA⁺ T Cells Synergize in Response to Alloantigens

Eur J Immunol

(1991)

A.J. McKnight et al.

Molecular Cloning of Rat Interleukin 4 cDNA and Analysis of the Cytokine Repertoire of Subsets of CD4⁺ T Cells

Eur J Immunol

(1991)

W.T. Lee et al.

Functional and Ontogenetic Analysis of Murine CD45R^hi and CD45R^lo CD4⁺ T Cells

J Immunol

(1990)

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IL-12 and IL-4 are the key differentiation-inducing stimuli for Th1 and Th2 cells, respectively. Th1 cells synthesize IL-2, TNF-α, and IFN-γ which can activate cellular immune response.18 Th2 cells usually produce IL-4, IL-5, IL-6, and IL-10, and participate in the regulation of humoral immunity.18
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CD4<sup>+</sup> regulatory T cells in autoimmunity and allergy
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Regulatory T cells (also referred to as suppressor T cells) are important components of the homeostasis of the immune system, as impaired regulatory T cell activity can cause autoimmune diseases and atopy. It is now clear that the phrase ‘regulatory T cells’ encompasses more than one cell type. For instance, CD4⁺CD25⁺ regulatory T cells have received attention due to their immunosuppressive properties in vitro and in vivo, but in several instances it has been shown that CD4⁺CD25⁻ T cell populations also contain potent regulatory activity. Recent progress in the field of regulatory T cells includes the discovery of the role of two tumor necrosis factor receptor (TNFR) family members (GITR and TRANCE-R/RANK) in Treg biology, the improved understanding of the role of co-stimulatory molecules and cytokines IL-10 and IL-2 in the induction and function of Tregs, and the generation of CD25⁺ and CD25⁻ regulatory T cells in vivo through high-avidity T cell receptor interactions.
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Nitric oxide (NO) is cytotoxic and cytostatic to blood stage malaria parasites in vitro, but the precise mechanism(s) by which it mediates an effect in vivo is not known. In particular, whether or not control of acute parasitemia depends on the presence of NO is unclear. We have shown previously that blocking NO synthesis at the time of its induction may cause an increase in peak primary parasitemia during infection of mice with Plasmodium chabaudi, suggesting that NO may be parasiticidal in vivo. However, as recent data indicate that NO suppresses Th1 cell proliferation in vitro by downregulating IL-2 production, we have investigated whether this immunoregulatory function of NO affects its capacity for anti-malarial activity. Treatment of P. chabaudi-infected mice with the iNOS inhibitor aminoguanidine hemisulfate (AG) starting just prior to the peak of primary parasitemia caused a significant elevation and extension of the acute infection and led to a partial but significant abrogation of the suppression of spleen cell proliferation to both mitogen and specific antigen observed when NO synthesis was not blocked. In the absence of NO, levels of IL-2, but not of IFN-γ, TNF-α, or of any Th2-regulated cytokines examined, increased significantly. However, when AG treatment was brought forward to the early ascending phase of primary parasitemia, significantly increased levels of IFN-γ and TNF-α, as well as of IL-2, were observed over those for infected control mice similarly treated with phosphate-buffered saline. Moreover, despite the absence of NO, parasitemias of AG-treated mice were not significantly elevated. The effect of AG therefore appeared to be dependent upon the timing of its administration in vivo. We propose that during malaria infections, there is a dynamic balance between the regulatory and anti-parasitic roles of NO. While the immunosuppressive function of NO leads to a downregulation in vivo of production of IL-2, and indirectly of IFN-γ and TNF-α, this perceived weakening of the host cell-mediated immune response is in part masked by the protective anti-malarial effects of NO itself.
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Poly I:C, an inducer of IFN-α and other cytokines, has been used to study the development of diabetes in both the BioBreeding (BB) diabetes prone rat and non-obese diabetic (NOD) mouse animal models of insulin-dependent diabetes mellitus (IDDM). Surprisingly, poly I:C accelerates the disease in the BB rat while inhibiting it in the NOD mouse. Since cytokines can have dose related opposing effects on immune responses, we hypothesized that the paradoxical effect of polyinosinic polycytidylic acid (poly I:C) on diabetes in the two animal models is dose related. Accordingly, we compared the incidence of diabetes and degree of insulitis in diabetes prone BB rats administered saline and poly I:C at doses (0.05 μg/g body weight and 0.1 μg/g body weight) up to 100-fold lower than doses (poly-5 μg/g) previously found to accelerate diabetes. In addition, the non-specific suppressor activity of mononuclear splenocytes from BB rats administered low dose (poly-0.05 μg/g body weight), high dose (poly-5 μg/g body weight), and saline were compared. The development of diabetes was inhibited in rats treated with each dose of poly I:C. The degree of insulitis in poly-I:C treated animals was also less severe. The total white blood cell count and proportion of RT6⁺T-cells and each T-cell subset were unaltered by poly I:C. When compared to splenocytes of control animals, splenocytes from poly I:C (0.05 μg/g body weight) treated rats suppressed responder cell proliferation to concanavalin A and alloantigen. However, spleen cells from high dose poly-I:C did not suppress responder cell proliferation to alloantigen. In adoptive transfer studies, the administration of spleen cells from poly-0.05 treated rats decreased the development of diabetes in recipient BB rats.In vitrostudies also demonstrated that poly-I:C inhibits the proliferative response of BB rat spleen cells to concanavalin A. The administration of poly-0.05, but not poly-5.0, decreased TNF-α mRNA and IL-10 mRNA content in spleen cells. We conclude that poly I:C, at a dose 100 times lower than that required to accelerate diabetes prevents the development of diabetes in BB rates by interfering with the development of insulitis. The induction of suppressor cell activity induced by low dose poly-I:Cin vivoand the inhibition of T-cell responses by poly-I:Cin vitrosuggests that the diabetes sparing activity of poly I:C is mediated by augmented immunoregulatory cell activity. Further studies with poly I:C may be important in increasing our understanding of the pathogenesis of IDDM and provide a means to prevent it.

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¹: D Mason and D Fowell, MRC Cellular Immunology Unit, Sir William Dun School of Pathology, Oxford OX1 3RE, UK.

View full text

T-cell subsets in autoimmunity

Abstract

Res Immunol

Immunol Rev

Biochem Soc Transactions

J Clin Invest

OX-22high CD4+ T Cells Induce Wasting Disease with Multiple Organ Pathology: Prevention by the OX-22low Subset

J Exp Med

Subsets of CD4+ T Cells and their Roles in the Induction and Prevention of Autoimmunity

Immunol Rev

Induction of Th1 and Th2 CD4+ Subsets during Murine Leishmania Major Infection

Res Immunol

IL-4 Induces a Th2 Response in Leisbmania Major-infected Mice

J Immunol

Mice Naturally Tolerant to C5 have T Cells that Suppress the Response to this Antigen

Eur J Immunol

Self Tolerance and Localized Immunity. Mouse Models of Autoimmune Disease that Suggest Tissue-specific Suppressor T Cells are Involved in Self Tolerance

J Exp Med

Suppression of Efferent Limb of Testicular Autoimmune Response by a Regulatory CD4+ T Cell Line in Mice

Clin Exp Immunol

Staphylococcal Enterotoxin-activated Spleen Cells Passively Transfer Diabetes in BB/Wor Rat

Diabetes

Human Thl and Th2: Doubt No More

Immunol Today

Purified Protein Derivative of Mycobacterium Tuberculosis and Excretory-Secretory Antigen(s) of Toxocara Canis Expand In Vitro Human T Cells with Stable and Opposite (Type 1 T Helper or Type 2 T Helper) Profile of Cytokine Production

J Clin Invest

Th1 and Th2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional Properties

Ann Rev Immunol

Postthymic T Cell Development in Rats: an Update

Biocbem Soc Transactions

Human CD4+CD45RO+ and CD4+ CD45RA+ T Cells Synergize in Response to Alloantigens

Eur J Immunol

Molecular Cloning of Rat Interleukin 4 cDNA and Analysis of the Cytokine Repertoire of Subsets of CD4+ T Cells

Eur J Immunol

Functional and Ontogenetic Analysis of Murine CD45Rhi and CD45Rlo CD4+ T Cells

J Immunol

OX-22high CD4⁺ T Cells Induce Wasting Disease with Multiple Organ Pathology: Prevention by the OX-22^low Subset

Subsets of CD4⁺ T Cells and their Roles in the Induction and Prevention of Autoimmunity

Induction of Th1 and Th2 CD4⁺ Subsets during Murine Leishmania Major Infection

Suppression of Efferent Limb of Testicular Autoimmune Response by a Regulatory CD4⁺ T Cell Line in Mice

Human CD4⁺CD45RO⁺ and CD4⁺ CD45RA⁺ T Cells Synergize in Response to Alloantigens

Molecular Cloning of Rat Interleukin 4 cDNA and Analysis of the Cytokine Repertoire of Subsets of CD4⁺ T Cells

Functional and Ontogenetic Analysis of Murine CD45R^hi and CD45R^lo CD4⁺ T Cells