Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome

Jain, Ashish; Atkinson, T. Prescott; Lipsky, Peter E.; Slater, Jay E.; Nelson, David L.; Strober, Warren

doi:10.1172/jci5891

Cited by 105 publications

(84 citation statements)

References 45 publications

(30 reference statements)

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“…The present study demonstrates that 1) the lack of CD40L signal, in vivo, in two hyper-IgM patients, is not strictly correlated with a CD8 ϩ deficiency, but rather with a defective number of CD45RO ϩ T cells reported as memory T cells. This is confirmed by a recent study where reduced Ag-primed population has been observed in both CD4 ϩ and CD8 ϩ populations, as determined by CD45RO expression (39 ϩ T cell proliferation. In DC-PBL cocultures, both CD86 and CD80 expressions were inhibited by the CD40 triggering of MV-infected DCs.…”

Section: Figure 2 Effect Of MV Replication On Cd40l-dependent Cd8supporting

confidence: 86%

Measles Virus Induces Abnormal Differentiation of CD40 Ligand-Activated Human Dendritic Cells

Servet-Delprat¹,

Vidalain²,

Bausinger

et al. 2000

The Journal of Immunology

154

179

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Measles virus (MV) infection induces a profound immunosuppression responsible for a high rate of mortality in malnourished children. MV can encounter human dendritic cells (DCs) in the respiratory mucosa or in the secondary lymphoid organs. The purpose of this study was to investigate the consequences of DC infection by MV, particularly concerning their maturation and their ability to generate CD8+ T cell proliferation. We first show that MV-infected Langerhans cells or monocyte-derived DCs undergo a maturation process similarly to the one induced by TNF-α or LPS, respectively. CD40 ligand (CD40L) expressed on activated T cells is shown to induce terminal differentiation of DCs into mature effector DCs. In contrast, the CD40L-dependent maturation of DCs is inhibited by MV infection, as demonstrated by CD25, CD69, CD71, CD40, CD80, CD86, and CD83 expression down-regulation. Moreover, the CD40L-induced cytokine pattern in DCs is modified by MV infection with inhibition of IL-12 and IL-1α/β and induction of IL-10 mRNAs synthesis. Using peripheral blood lymphocytes from CD40L-deficient patients, we demonstrate that MV infection of DCs prevents the CD40L-dependent CD8+ T cell proliferation. In such DC-PBL cocultures, inhibition of CD80 and CD86 expression on DCs was shown to require both MV replication and CD40 triggering. Finally, for the first time, MV was shown to inhibit tyrosine-phosphorylation level induced by CD40 activation in DCs. Our data demonstrate that MV replication modifies CD40 signaling in DCs, thus leading to impaired maturation. This phenomenon could play a pivotal role in MV-induced immunosuppression.

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Section: Figure 2 Effect Of MV Replication On Cd40l-dependent Cd8supporting

confidence: 86%

Measles Virus Induces Abnormal Differentiation of CD40 Ligand-Activated Human Dendritic Cells

Servet-Delprat¹,

Vidalain²,

Bausinger

et al. 2000

The Journal of Immunology

154

179

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“…In turn, we surmise that under physiological circumstances, costimulation is likely to be critical to achieve full T cell activation. In support of this, there is a markedly reduced Ag-primed population in people suffering from mutations in the gene encoding for CD40 ligand (47). In corneal transplantation, some evidence has been provided suggesting that the cytotoxic activity of CD8 ϩ T cells is impaired (48).…”

Section: Discussionmentioning

confidence: 96%

Role of CD4+ and CD8+ T Cells in Allorecognition: Lessons from Corneal Transplantation

Boisgerault

Liu

Anosova

et al. 2001

The Journal of Immunology

110

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Corneal transplantation represents an interesting model to investigate the contribution of direct vs indirect Ag recognition pathways to the alloresponse. Corneal allografts are naturally devoid of MHC class II+ APCs. In addition, minor Ag-mismatched corneal grafts are more readily rejected than their MHC-mismatched counterparts. Accordingly, it has been hypothesized that these transplants do not trigger direct T cell alloresponse, but that donor Ags are presented by host APCs, i.e., in an indirect fashion. Here, we have determined the Ag specificity, frequency, and phenotype of T cells activated through direct and indirect pathways in BALB/c mice transplanted orthotopically with fully allogeneic C57BL/6 corneas. In this combination, only 60% of the corneas are rejected, while the remainder enjoy indefinite graft survival. In rejecting mice the T cell response was mediated by two T cell subsets: 1) CD4+ T cells that recognize alloantigens exclusively through indirect pathway and secrete IL-2, and 2) IFN-γ-producing CD8+ T cells recognizing donor MHC in a direct fashion. Surprisingly, CD8+ T cells activated directly were not required for graft rejection. In nonrejecting mice, no T cell responses were detected. Strikingly, peripheral sensitization to allogeneic MHC molecules in these mice induced acute rejection of corneal grafts. We conclude that only CD4+ T cells activated via indirect allorecognition have the ability to reject allogeneic corneal grafts. Although alloreactive CD8+ T cells are activated via the direct pathway, they are not fully competent and cannot contribute to the rejection unless they receive an additional signal provided by professional APCs in the periphery.

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“…Humans and mice with CD40L deficiency have a diminished capacity to prime T cells and induce the memory T cell phenotype (17,18). Antigen priming of T cells is associated with a change in the T cell CD45 isoform: human naïve T cells express the CD45RA isoform, whereas antigen-primed human memory T cells express the CD45RO isoform (29).…”

Section: Analysis Of Rankl Expression and Ifn-␥ Production By Activatmentioning

confidence: 99%

“…IL-12 secretion by APCs leads to the differentiation of naïve T cells into T H 1 effector cells capable of producing IFN-␥. The importance of this interaction has been shown in both humans and mice with CD40L deficiency, where the population of antigenprimed memory T cells is markedly diminished, and activated T cells fail to secrete IFN-␥ or induce IL-12 secretion in APCs (17,18). Clinically, such impairments in T cell immunity predispose XHIM patients to opportunistic infections with Pneumocystis carinii and Cryptosporidium (19)(20)(21).…”

mentioning

confidence: 99%

Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis

López‐Granados

Temmerman

et al. 2007

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

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Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome

Cited by 105 publications

References 45 publications

Measles Virus Induces Abnormal Differentiation of CD40 Ligand-Activated Human Dendritic Cells

Measles Virus Induces Abnormal Differentiation of CD40 Ligand-Activated Human Dendritic Cells

Role of CD4+ and CD8+ T Cells in Allorecognition: Lessons from Corneal Transplantation

Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis

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