Impaired thymic negative selection causes autoimmune graft-versus-host disease

Teshima, Takanori; Reddy, Pavan; Liu, Chen; Williams, Debra; Cooke, Kenneth R.; Ferrara, James L.M.

doi:10.1182/blood-2003-01-0266

Cited by 89 publications

(74 citation statements)

References 61 publications

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“…1A) (3). In contrast, we observed massive expansion of lymphocytic choriomeningitis virus (LCMV) GP [33][34][35][36][37][38][39][40][41] CD8 + T cells in CD4 + T-cell-depleted mice, which lack both regulatory and conventional CD4 + T cells (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Muth

Schütze

Schild

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Resting dendritic cells (DCs) induce tolerance of peripheral T cells that have escaped thymic negative selection and thus contribute significantly to protection against autoimmunity. We recently showed that CD4 + Foxp3+ regulatory T cells (Tregs) are important for maintaining the steady-state phenotype of DCs and their tolerizing capacity in vivo. We now provide evidence that DC activation in the absence of Tregs is a direct consequence of missing DC-Treg interactions rather than being secondary to generalized autoimmunity in Treg-less mice. We show that DCs that lack MHC class II and thus cannot make cognate interactions with CD4 + T cells are completely unable to induce peripheral CD8 + T-cell tolerance. Consequently, mice in which interactions between DC and CD4 + T cells are not possible develop spontaneous and fatal cytotoxic T lymphocyte-mediated autoimmunity. DCs are bone marrow (BM)-derived, short-lived cells that play a key role in regulating immune responses. They are located at low frequency in lymphoid and nonlymphoid organs throughout the body, where they act as sentinels for invading pathogens. On recognition of pathogen-associated cues, DCs undergo a series of functional changes termed maturation, which is characterized by the up-regulation of costimulatory molecules such as CD80, CD86, and CD70, by the production of cytokines, such as IL-12, and by the expression of homing receptors, such as CCR7, that direct DC migration into the T-cell areas of secondary lymphoid organs. Together these changes allow DCs to efficiently activate naive T cells.Over the past decade, it has become clear that steady-state DCs play an important role in the maintenance of self-tolerance (1-3) and T-cell responsiveness (4). Because DCs can either prime or tolerize naive T cells, depending on their activation status, they are master regulators of adaptive immunity. How the maturation status of DCs translates into differential effects on naive T cells involves a variety of costimulatory and coinhibitory interactions between T cells and DCs. For example, we showed that tolerance induction depends on PD-1 and CTLA-4 (5), whereas blockade of CD70, a costimulatory molecule that is upregulated on activated DCs, prevents priming of CD8 + T cells even in the context of an infection (6). Along the same line, constitutive transgenic expression of CD70 on all DCs prevents the induction of tolerance and results in priming of a functional T-cell response by steady-state DCs (7).DC maturation can be triggered by numerous exogenous and endogenous stimuli that are usually associated with infection, inflammation, or damage (8 (10)(11)(12)(13)(14). Tregs may control self-reactive T-cell responses by direct interaction with conventional T cells or, alternatively, may act on DCs (15). Evidence for the latter comes from experiments in which depletion of Tregs results in Flt3-dependent increases in the number of DCs as well as in DC activation (9,11,16).When we combined the DIETER model of peripheral tolerance induction by steady-state DCs a...

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Section: Resultsmentioning

confidence: 99%

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Muth

Schütze

Schild

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…47 The other mechanism is aberrant thymopoiesis, leading to impaired negative selection of autoreactive clones derived from donor stem cells and/or reduced generation of regulatory T cells. [48][49][50][51][52] The influence of this mechanism has recently been evidenced in the clinical setting, as T-cell depletion of allografts could not reduce the incidence of chronic GVHD. 53 It is conceivable that the higher number of CD34 þ cells in PBSC could generate more autoreactive post-thymic T cells, thereby increasing the risk of chronic GVHD and confounding the contribution of alloreactive CCR7 þ donor T cells.…”

Section: Tablementioning

confidence: 99%

A high proportion of donor CD4+ T cells expressing the lymph node-homing chemokine receptor CCR7 increases incidence and severity of acute graft-versus-host disease in patients undergoing allogeneic stem cell transplantation for hematological malignancy

et al. 2006

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CC-chemokine receptor 7 (CCR7), a chemokine receptor required for transmigration into lymphoid organs, is only expressed by naive and central memory T cells. T cells with a capacity of homing into lymphoid organs can initiate acute graft-versus-host disease (GVHD) in mice and respond vigorously in vitro to alloantigens in humans, but their impact on clinical outcomes is unknown. We evaluated prospectively the distribution of naive, central memory and CCR7 neg memory T-cell subsets in 39 bone marrow and 23 granulocyte colonystimulating factor-mobilized peripheral blood stem cell allografts and investigated their impact on patient outcomes. Ranges of the relative proportions of CCR7 þ cells within CD4 þ and CD8 þ T-cell populations were broad, but did not differ between the two sources of allografts. By multivariate analysis, high percentage of donor-derived CD4 þ CCR7 þ T cells (473.5%) significantly correlated with incidence, earliness of onset and severity of acute GVHD, conferring the highest adjusted hazard ratio (HR ¼ 3.9; 95% confidence interval 1.4-10.8; P ¼ 0.008) without interfering in other clinical events, especially chronic GVHD and relapse. Determination of the percentage of CD4 þ CCR7 þ T cells in the graft provides a predictive indicator of acute GVHD. Partial depletion of this subset may reduce the risk of acute GVHD while preserving immunotherapeutic effects.

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“…2 Impairment of thymic function observed in patients with cGVHD 3 could lead to the release into the periphery of T cells with autoreactive potential. 4 Although such perturbations in central tolerance may be important, data relating to experimental autologous GVHD induction 5 or to models in which thymic, negative selection is prevented, 6 suggest that autoreactive T cells only induce tissue injury when there are additional defects in peripheral tolerance.…”

Section: Introductionmentioning

confidence: 99%

Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells

Clark

Gregg

Piper

et al. 2004

Blood

194

117

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Chronic graft-versus-host disease (cGVHD) is characterized by a state of profound immunodeficiency in association with alloreactive and autoimmune phenomena. These observations indicate an impairment of immunologic tolerance that could involve both central and peripheral mechanisms. Defective thymic function may contribute to dysregulation of central tolerance, but few studies have addressed peripheral tolerance. Recently a population of CD4 ؉ CD25 ؉ T cells (T reg cells) has been characterized, which controls immunologic reactivity in vivo and which on transfer can prevent experimental acute GVHD. We investigated the number and function of peripheral blood CD4 ؉ CD25 high T cells in patients more than 100 days after allogeneic hematopoietic stem cell transplantation. Patients with cGVHD had markedly elevated numbers of CD4 ؉ CD25 high T cells as compared to patients without GVHD. CD4 ؉ CD25 high T cells derived from patients in both groups were of donor origin, lacked markers of recent activation, and expressed intracellular CD152. In contrast to controls, CD4 ؉ CD25 high T cells derived from patients with cGVHD were characterized by lower surface CD62L expression. In vitro, CD4 ؉ CD25 high T cells were hyporesponsive to polyclonal stimulation and suppressed the proliferation and cytokine synthesis of CD4 ؉ CD25 ؊ cells, an effect that was independent of interleukin 10. These results indicate that chronic graft-versus-host injury does not occur as a result of T reg cell deficiency. IntroductionChronic graft-versus-host disease (cGVHD) remains the most frequent complication following allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 30% to 70% of long-term survivors. 1 Profound immune dysregulation leads to both immunodeficiency and autoimmunity, suggesting defects in central or peripheral immunologic tolerance. 2 Impairment of thymic function observed in patients with cGVHD 3 could lead to the release into the periphery of T cells with autoreactive potential. 4 Although such perturbations in central tolerance may be important, data relating to experimental autologous GVHD induction 5 or to models in which thymic, negative selection is prevented, 6 suggest that autoreactive T cells only induce tissue injury when there are additional defects in peripheral tolerance.Recently a population of naturally occurring regulatory CD4 ϩ T cells (T reg cells) that constitutively express the ␣ chain of the receptor for interleukin 2 (IL-2; CD25) has been characterized that can suppress immune responses both in vitro and in vivo (for reviews, see Maloy and Powrie, 7 Shevach, 8 and Wood and Sakaguchi 9 ). In humans, T reg cells appear to be enriched within the 1% to 2% of peripheral blood CD4 ϩ T cells that are CD25 high10 and in vitro, inhibit the function of effector T cells via a mechanism that requires prior T-cell activation, involves cell-to-cell contact, and is independent of cytokine secretion. [11][12][13][14][15][16] In contrast, in vivo studies indicate that cytokines such as IL-10 or transfor...

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Impaired thymic negative selection causes autoimmune graft-versus-host disease

Cited by 89 publications

References 61 publications

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

A high proportion of donor CD4+ T cells expressing the lymph node-homing chemokine receptor CCR7 increases incidence and severity of acute graft-versus-host disease in patients undergoing allogeneic stem cell transplantation for hematological malignancy

Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells

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Impaired thymic negative selection causes autoimmune graft-versus-host disease

Cited by 89 publications

References 61 publications

Release of dendritic cells from cognate CD4+T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Release of dendritic cells from cognate CD4+T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

A high proportion of donor CD4+ T cells expressing the lymph node-homing chemokine receptor CCR7 increases incidence and severity of acute graft-versus-host disease in patients undergoing allogeneic stem cell transplantation for hematological malignancy

Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells

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Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity