Defective Expression of CD40 Ligand on T Cells Causes “X‐Linked Immunodeficiency with Hyper‐IgM (HIGM1)”
TL;DR: A combination of structural and functional analyses finally demonstrated that the failure of TRAP/CD40L on T cells to interact with CD40 on B cells is responsible for the inefficient T-cell help for B cells observed in HIGM1.
Abstract: X-linked immunodeficiency with hyper-IgM (HIGM1) is a rare disorder, characterized by recurrent infections associated with very low or absent IgG and IgA, and normal to increased IgM serum levels. The disease has been earlier mapped to the q26-27 region of the X-chromosome. We have identified a novel molecule expressed on the surface of activated T cells, which was designated TRAP (Tumor necrosis factor Related Activation Protein), and could demonstrate that TRAP is a ligand for the CD40 receptor expressed on B cells. Our mapping of the TRAP gene to the Xq26.3-27.1 region suggested a causal relationship to HIGM1. Further work revealed that various mutations of the TRAP/CD40 ligand (CD40L) gene may lead to a defective expression of the TRAP/CD40L molecule on the T-cell surface in HIGM1 patients. A combination of structural and functional analyses finally demonstrated that the failure of TRAP/CD40L on T cells to interact with CD40 on B cells is responsible for the inefficient T-cell help for B cells observed in HIGM1. The observations made in HIGM1 allowed us to conclude that TRAP/CD40L is not required for IgM synthesis. In contrast, functional expression of TRAP is a prerequisite for effective immunoglobulin isotype switching and subsequent production of IgG, IgA and IgE by B cells in vivo. The interaction of TRAP/CD40L with CD40 thus provides a very critical link between the cellular and the humoral part of the immune system. The knowledge of TRAP/CD40L cDNA sequence, the availability of various reagents for the testing of expression and function of TRAP/CD40L, and our recent elucidation of the exon-intron structure of the TRAP/CD40L gene now provide all necessary tools for early diagnosis of affected patients and the detection of female carriers of HIGM1. The available information will also provide a basis for future attempts at gene therapy in this disease.
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TL;DR: In this paper, platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo, indicating that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.
Abstract: CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, was originally identified on stimulated CD4+ T cells, and later on stimulated mast cells and basophils. Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system. CD40 is not only constitutively present on B cells, but it is also found on monocytes, macrophages and endothelial cells, suggesting that CD40L has a broader function in vivo. We now report that platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo. Like TNF-alpha and interleukin-1, CD40L on platelets induces endothelial cells to secrete chemokines and to express adhesion molecules, thereby generating signals for the recruitment and extravasation of leukocytes at the site of injury. Our results indicate that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.
2,045 citations
Cites background from "Defective Expression of CD40 Ligand..."
...Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune syste...
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TL;DR: The identification of a third member of this family of molecules, inducible co-stimulator (ICOS), which is a homodimeric protein of relative molecular mass 55,000–60,000 (Mr 55K–60K) indicates that ICOS is another major regulator of the adaptive immune system.
Abstract: The T-cell-specific cell-surface receptors CD28 and CTLA-4 are important regulators of the immune system. CD28 potently enhances those T-cell functions that are essential for an effective antigen-specific immune response, and the homologous CTLA-4 counterbalances the CD28-mediated signals and thus prevents an otherwise fatal overstimulation of the lymphoid system. Here we report the identification of a third member of this family of molecules, inducible co-stimulator (ICOS), which is a homodimeric protein of relative molecular mass 55,000-60,000 (M(r) 55K-60K). Matching CD28 in potency, ICOS enhances all basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, upregulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells. Unlike the constitutively expressed CD28, ICOS has to be de novo induced on the T-cell surface, does not upregulate the production of interleukin-2, but superinduces the synthesis of interleukin-10, a B-cell-differentiation factor. In vivo, ICOS is highly expressed on tonsillar T cells, which are closely associated with B cells in the apical light zone of germinal centres, the site of terminal B-cell maturation. Our results indicate that ICOS is another major regulator of the adaptive immune system.
1,479 citations
Cites background from "Defective Expression of CD40 Ligand..."
...Co-stimulation of T cells through ICOS or CD28 markedly upregulated expression of CD154 (also known as CD40 ligand or TRAP), a molecule required for the crosstalk of T cells with B cell...
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TL;DR: The phenotype of human ICOS deficiency, which differs in key aspects from that of the ICOS−/− mouse, suggests a critical involvement of ICOS in T cell help for late B cell differentiation, class-switching and memory B cell generation.
Abstract: No genetic defect is known to cause common variable immunodeficiency (CVID), a heterogeneous human disorder leading to adult-onset panhypogammaglobulinemia. In a search for CVID candidate proteins, we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene. T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast, naive, switched and memory B cells were reduced. The phenotype of human ICOS deficiency, which differs in key aspects from that of the ICOS-/- mouse, suggests a critical involvement of ICOS in T cell help for late B cell differentiation, class-switching and memory B cell generation.
715 citations
TL;DR: Adoptively transferred antigen-specific CD4+ T cells lacking CD40L failed to expand upon antigen challenge of the recipients, showing that expression ofCD40L on T cells is required for in vivo priming of CD4 + T cells and therefore for the initiation of specific T-cell immune responses.
Abstract: LACK of functional expression of CD40 ligand (CD40L) on T cells results in hyper-IgM syndrome (HIGMl), a human immunodeficiency associated with a severely impaired humoral immune response that is consistent with defects in B-cell responses1–3. Patients also succumb to recurrent opportunistic infections such as Pneumocystis carinii and Cryptosporidial diarrhoea4,5, suggesting that T-cell functions are also compromised in these individuals, but so far this has not been explained. We have previously shown that mice deficient for CD40L, like HIGMl patients, show grossly abnormal humoral responses6. Here we report that CD40L-deficient mice are defective in antigen-specific T-cell responses. Adoptively transferred antigen-specific CD4+ T cells lacking CD40L failed to expand upon antigen challenge of the recipients, showing that expression of CD40L on T cells is required for in vivo priming of CD4+ T cells and therefore for the initiation of specific T-cell immune responses.
491 citations
TL;DR: The findings indicate that the interaction of platelet CD154 with CD40 on neighboring cells is temporally limited to prevent an uncontrolled inflammation at the site of thrombus formation.
428 citations
References
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TL;DR: It appears now that TNF rarely induces in vivo direct cytolysis of natural tumors, that it may not play a significant role in the cachexia most commonly observed in humans, that resulting from cancer, and that the critical role of TNF in shock is shared by other mediators, particularly interleukin 1 (ILl ), its frequent com-
Abstract: Tumor necrosis factor (TNF) came to birth in a strange way. It made its entry into the world of biology and medicine when Lloyd Old discovered that the capacity to induce, in vivo and in vitro, the necrosis of some mouse tumors could be ascribed to a factor (rapidly identified as a protein) present in the blood after LPS injection ( 1 ) . Then, at what may appear as an unsurmountable biological distance but what geographically was a very close event (occurring in New York City virtually on the other side of the street), Anthony Cerami discovered that the intriguing state of cachexia associated with hypertriglyceridemia presented by rabbits chronically infected with Trypanosomia brucei results from the presence of a serum protein which he called "cachectin." Purification of cachectin by A. Cerami and B. Beutler led them to realize that it is also an essential mediator in the state of shock induced by LPS injection in mice and is the same molecule as TNF (2, 3). It required little time for these three parents to recognize that their common child, with its so disparate talents, was unusually gifted. What they could not foresee was that, within a very few years, TNF would turn out to be a child prodigy, eliciting, because of its diverse effects, the publication of several papers per day. Somewhat ironically, it appears now that TNF rarely induces in vivo direct cytolysis of natural tumors (it can even be made by them), that it may not play a significant role in the cachexia most commonly observed in humans, that resulting from cancer, and that the critical role of TNF in shock is shared by other mediators, particularly interleukin 1 (ILl ), its frequent com-
1,948 citations
"Defective Expression of CD40 Ligand..." refers background in this paper
...It is therefore conceivable that the TRAP protein is also secreted, as is the case with TNFa (Vassalli 1992)....
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TL;DR: The cloning of a ligand for CD40 that is expressed on the cell surface of activated T cells and mediates B-cell proliferation in the absence of co-stimulus, as well as IgE production in the presence of interIeukin-4 is reported.
Abstract: THE CD40 surface molecule is a 277-amino-acid glycoprotein expressed on B lymphocytes, epithelial cells and some carcinoma cell lines. Monoclonal antibodies against CD40 mediate a variety of effects on B lymphocytes, including induction of intercellular adhesion1,2, short- and long-term proliferation3–5, differentiation6,7 and enhanced tyrosine phosphorylation of proteins8. In addition, germinal centre centrocytes are prevented from undergoing apop-tosis by activation through CD40 and receptor for antigen9. These data indicate that CD40 could be a receptor for an unknown ligand with important functions in B-cell development and activation. This hypothesis is strengthened by the homology of the extracellular region of the CD40 molecule10with a family of cell-surface glycoproteins11,12that includes the receptors for nerve growth factor13,14 and tumour necrosis factor11,15,16. Here we report the cloning of a ligand for CD40 that is expressed on the cell surface of activated T cells and mediates B-cell proliferation in the absence of co-stimulus, as well as IgE production in the presence of interIeukin-4.
1,136 citations
TL;DR: Data indicate that the 39-kDa membrane protein expressed on activated Th is a binding protein for CD40 and functions to transduce the signal for Th-dependent B-cell activation.
Abstract: CD40 is a B-cell surface molecule that has been shown to induce B-cell growth upon ligation with monoclonal antibodies. This report shows that triggering via CD40 is essential for the activation of resting B cells by helper T cells (Th). A soluble fusion protein of CD40 and human immunoglobulin, CD40-Ig, inhibited the induction of B-cell cycle entry, proliferation, and differentiation by activated Th1 and Th2. The ligand for CD40 was identified as a 39-kDa membrane protein that was selectively expressed on activated Th. A monoclonal antibody specific for the 39-kDa protein inhibited CD40-Ig binding and also inhibited the activation of B cells by Th. These data indicate that the 39-kDa membrane protein expressed on activated Th is a binding protein for CD40 and functions to transduce the signal for Th-dependent B-cell activation.
853 citations
"Defective Expression of CD40 Ligand..." refers background in this paper
...The critical role of CD40 was also demonstrated by inhibiting T-helper induced B-cell proliferation using soluble CD40 molecules (Noelle et al. 1992)....
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TL;DR: It is reported that patients with hyper-IgM syndrome (HIM) have a defective gp39-CD40 interaction, which suggests that a defect in gp39 is the basis of X-linked HIM.
840 citations
TL;DR: Abnormalities in the CD40L gene were associated with an X-linked immunodeficiency in humans [hyper-IgM (immunoglobulin M) syndrome], characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes.
Abstract: The ligand for CD40 (CD40L) is a membrane glycoprotein on activated T cells that induces B cell proliferation and immunoglobulin secretion. Abnormalities in the CD40L gene were associated with an X-linked immunodeficiency in humans [hyper-IgM (immunoglobulin M) syndrome]. This disease is characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. CD40L complementary DNAs from three of four patients with this syndrome contained distinct point mutations. Recombinant expression of two of the mutant CD40L complementary DNAs resulted in proteins incapable of binding to CD40 and unable to induce proliferation or IgE secretion from normal B cells. Activated T cells from the four affected patients failed to express wild-type CD40L, although their B cells responded normally to wild-type CD40L. Thus, these CD40L defects lead to a T cell abnormality that results in the failure of patient B cells to undergo immunoglobulin class switching.
831 citations