The JI PBL Intereron Source
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lobo, F. M.
Right arrow Articles by Fuleihan, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lobo, F. M.
Right arrow Articles by Fuleihan, R. L.
The Journal of Immunology, 2002, 168: 1473-1478.
Copyright © 2002 by The American Association of Immunologists

CD40 Ligand-Deficient T Cells from X-Linked Hyper-IgM Syndrome Carriers Have Intrinsic Priming Capability1

Francis M. Lobo2,{dagger}, Paul R. Scholl{ddagger} and Ramsay L. Fuleihan*

Departments of * Pediatrics and {dagger} Internal Medicine, Yale Child Health Research Center and Sections of Immunology, Yale University School of Medicine, New Haven, CT 06520; and {ddagger} Disease Pathogenesis Program, Department of Pediatrics, Children’s Memorial Institute for Education and Research, Northwestern University Medical School, Chicago, IL 60614


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Deficiency in CD40 ligand (CD40L) expression is associated with impaired T cell immunity in mouse models and in humans. Previous studies have indicated that this is due to the failure of induction of extrinsic costimulatory molecules. However, other studies have suggested that CD40L is an intrinsic costimulatory molecule. The X-linked hyper-IgM syndrome (XHIM) is a primary immunodeficiency caused by mutations in CD40L, resulting in impaired Ab production and T cell immunity. CD4+ T cells from female carriers of XHIM express a variable degree of normal CD40L based on random X chromosome inactivation. We have examined T cells from XHIM carriers to investigate whether CD40L supports T cell function by acting as an intrinsic costimulator or by induction of other costimulatory molecules by examining coexpression of CD40L and markers of T lymphocyte priming. These carriers provide a unique model for comparison of CD40L-expressing and -nonexpressing lymphocytes in that all factors, including immunological experience, are equivalent between the two populations. Our results show that compared with CD40L-deficient T cells, T cells that express CD40L normally have a minimal advantage in becoming primed, as defined by CD45 RO isoform expression and production of IFN-{gamma} and TNF-{alpha}. Conversely, CD40L-deficient T lymphocytes clearly were capable of becoming primed as defined by the same parameters. These findings imply that the intrinsic costimulatory activity of CD40L is not required for attaining primed status, and that CD40L primarily supports T cell function by inducing extrinsic factors that can be shared by CD40L-deficient cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A ligand that plays a critical role in the adaptive immune response is the CD40 ligand (CD40L,3 CD154). The requirement for CD40L both in Ab-mediated and in T cell-mediated immunity is evident in the X-linked hyper-IgM syndrome (XHIM), a primary immune deficiency caused by mutations in CD40L, which is characterized by recurrent bacterial as well as T cell opportunistic infections (1). XHIM patients demonstrate a profound deficiency in Ab production due to the failure of CD40L-induced B cell maturation. However, unlike other primary humoral, XHIM patients display a high incidence of T cell opportunistic infections, particularly Pneumocystis carinii pneumonia and Cryptosporidium enteritis. These opportunistic infections provide clear in vivo evidence that CD40L is an essential mediator of T cell immunity.

The profound defect in T cell immunity among XHIM patients has been evident in in vitro studies. T cells from XHIM patients respond normally to mitogenic stimulation (1) but are markedly impaired in Ag priming as measured by CD45RO expression, by TNF-{alpha} and IFN-{gamma} production, and by the ability to induce IL-12 synthesis (2). In contrast to these findings, a recent study has demonstrated that T cells from XHIM patients show no difference in the ability to make TNF-{alpha}, IFN-{gamma}, IL-2, and IL-4 when compared with T cells from age-matched controls (3).

The critical nature of CD40L/CD40 signaling in T cell-mediated immunity also has been corroborated by studies using CD40L-deficient mice, as well as strategies to block CD40L/CD40 interactions. CD40L-deficient mice demonstrate defects in recall response to T cell-dependent Ags (4), in graft-vs-host disease (5), and in inducing experimental allergic encephalomyelitis (6). In addition, blockade of CD40L/CD40 prevents the usual recovery of immune-reconstituted SCID mice from Pneumocystis infection (7). Furthermore, Ab blockade of CD40L can impair T cell mediated inflammation, including graft-vs-host disease (8), rejection of solid organ transplants (9, 10), collagen-induced arthritis (11), and a murine model of lupus nephritis (12).

The induction of costimulatory molecules on CD40-bearing cells is one mechanism by which CD40L/CD40 interactions support T cell function. Ligation of CD40 by CD40L enhances expression of B7.1 and B7.2 molecules on B cells (13), dendritic cells (14), and monocytes (15). Subsequent costimulation of T cells by ligation of CD28 by B7.1 and B7.2 is required for effector T cell differentiation (16). Indeed, the ability to induce experimental allergic encephalomyelitis in CD40L-deficient mice can be restored by overexpression of B7 on APC (6). Furthermore, the capacity of B cells from CD40-deficient mice to induce tolerance to alloantigen can be abolished if the cells are stimulated to express B7 molecules by LPS (17). In addition to B7 molecules, CD40 ligation also stimulates production of a variety of cytokines, such as dendritic cell production of IL-12 (18). In this model, the costimulatory molecules and cytokines produced by CD40-bearing cells are extrinsic factors that can be shared by CD40L-deficient T cells in the same microenvironment (Fig. 1GoA).



View larger version (50K):
[in this window]
[in a new window]
  		FIGURE 1. Schematic representation of extrinsic model of CD40L-derived T cell help (A) and intrinsic model of CD40L-derived T cell help (B).

 
In addition to the induction of costimulatory molecules by CD40L, Brenner et al. (19) have provided evidence that CD40L itself might provide an intrinsic costimulatory signal to CD40L-expressing T cells. In their studies, mAb stimulation of CD40L leads to Rac1-dependent activation of Jun N-terminal kinase and p38 MAP kinase. CD40L stimulation also results in tyrosine phosphorylation of a variety of intracellular proteins, including PLC{gamma}, with subsequent activation of protein kinase C (20). Furthermore, the same group has determined that mAb stimulation of CD40L activates a neutral sphingomyelinase, leading to consumption of sphingomyelin and generation of ceramide (21), although the significance of this pathway in T cell activation is unknown. Elegant studies by van Essen, Poudrier, Gray, and colleagues (22, 23) have provided further evidence of the role of intrinsic signaling by CD40L in T cell effector function. Stimulation of CD40L by soluble CD40 in a CD40-/- mouse model restores initiation of germinal center formation (22) and enables optimal production of IL-4 by T cells (23). In this intrinsic model of CD40L-derived T cell help (Fig. 1GoB), any CD40L-deficient T cell would derive no benefit from these means of costimulation and consequently would be at a disadvantage in becoming Ag primed.

Although XHIM patients demonstrate profound defects in B cell- and T cell-mediated immunity, the female carriers of XHIM show little if any immune deficiency. Because CD40L deficiency is not lethal to developing T cells, the random inactivation of the X chromosome in female carriers leads to a mixed population of T cells bearing either normal or defective CD40L (24). We have tested female carriers of XHIM to ascertain whether the failure of T lymphocytes to express functional CD40L conveys an intrinsic inability to become primed, as measured by surface phenotype and the ability to secrete cytokines. Our model requires maximal stimulation of T cells, using phorbol ester and calcium ionophore, to induce CD40L expression on all cells capable of expressing it. Although such conditions of stimulation allow for full expression of CD40L, they induce expression of cytokines such as TNF-{alpha} and IFN-{gamma} only on T cells that have been primed by previous Ag stimulation (25). Therefore, coexpression of CD40L and cytokine reflects the contribution that CD40L makes to T cell priming.

Because CD40L-bearing and -deficient T cells in XHIM carriers have matured under identical conditions, the XHIM carriers provide a model for determining the relative advantage conveyed by CD40L in which factors beyond age, most notably immunological experience, are optimally controlled. This avoids the inaccuracies inherent in attempts at matching subjects with immunologically "normal" controls. Indeed, studies of the role of CD40L in T cell priming using patients and matched controls have generated sharply contrasting results (2, 3). The study by Jain et al. (2) indicates that CD40L-deficient T cells from XHIM patients are severely impaired in the ability to make cytokines compared with controls not matched by age. Using age-matched controls, Uronen et al. (3) have demonstrated that T cells from XHIM are equal and in some cases superior to control T cells in cytokine secretion. By examining XHIM carriers, our study addresses this question with a novel and optimal internal control.

Our results indicate that CD40L-expressing lymphocytes have only a minimal advantage over CD40L-deficient T lymphocytes in attaining a primed phenotype as defined by CD45 RO expression and the ability to produce TNF-{alpha} and IFN-{gamma}. There was no distinction in the ability to make IL-2. These data indicate that CD40L deficiency does not cause an intrinsic T cell priming defect. They also argue that any intracellular signaling by CD40L is not a requirement for T cell priming. However, these results stand in contrast with studies showing no advantage for CD40L-bearing T cells in cytokine production (3). As such, they provide insight into the mechanisms by which CD40L supports T cell immunity.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
XHIM carriers and controls

Five carriers of XHIM from different families were studied. The diagnosis of XHIM was made in a male relative of each by clinical criteria and/or by CD40L sequencing. Immunologically normal volunteer blood donors served as controls. Informed consent was obtained from all subjects under a protocol approved by the Human Investigation Committee of Yale University.

Lymphocyte preparation

PBMC were isolated from whole blood of XHIM carriers and controls by Ficoll density gradient centrifugation, and they were enriched for CD4+ cells by negative selection using affinity chromatography columns (IsoCell; Pierce, Rockford, IL), resulting in >97% purity of CD4+ cells as determined by flow cytometry.

Flow cytometry

CD4+ T cells were stimulated with 20 ng/ml PMA and 1.5 µM ionomycin for 6 h. They were assayed for cell surface expression of CD40L and CD45RA or CD45RO isoforms by flow cytometry on a FACScan (BD Biosciences, San Jose, CA) as described (26) using a PE-conjugated CD40L mAb and FITC-conjugated CD45 mAbs (BD PharMingen, San Diego, CA). Appropriate isotype control mAbs were used for background staining. The total percentage of CD40L+ cells was adjusted by multiplying the percentage of CD40L+ by the percentage of CD4+ purity.

Intracellular cytokine staining

FITC-conjugated IL-2, TNF-{alpha}, and IFN-{gamma} mAbs (BD PharMingen) were used for two-color staining. At 2 h before the end of the 6-h stimulation, monensin was added at a 2 µM final concentration. After staining for cell surface CD40L or isotype control, the cells were fixed by overnight incubation at 4°C in 2% paraformaldehyde in PBS. The cells then were washed twice with and resuspended in 100 µl of permeabilization buffer (0.1% saponin and 1% FCS, w/v, in PBS) followed by a 30-min incubation with FITC-conjugated mAbs against IL-2, TNF-{alpha}, IFN-{gamma}, or isotype controls. They then were washed in an excess volume of PBS and analyzed by flow cytometry.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
XHIM patient characteristics

The diagnosis of XHIM was made by clinical criteria and by the absence of detectable cell surface CD40L by flow cytometry in a male child of carriers 1, 2, 3, and 5, and in a brother of carrier 4. The brother of carrier 4 has been found to have a splice donor site mutation, leading to exon 3 deletion of CD40L (27). His sister’s carrier status was confirmed by RT-PCR, which demonstrated both the normal and the shortened form of CD40L that corresponds with her brother’s exon 3 deletion (data not shown). The clinical features of each XHIM patient indicate that each family’s mutation resulted in impairment of T cell-mediated immunity (Table IGo). Four of the five XHIM patients presented with Pneumocystis pneumonia. The XHIM carriers in our study had no clinical evidence of immune deficiency.


View this table:
[in this window]
[in a new window]
  		Table I. XHIM female carriers and affected male relatives

 
XHIM carriers have partial expression of CD40L

CD4+ T cells from XHIM carriers were stimulated with a dose of PMA (20 ng/ml) and ionomycin (1.5 µM) that induces CD40L expression on 95–100% of CD4+ T cells from an immunologically normal control (Fig. 2Go). Based on this degree of CD40L expression after PMA and ionomycin stimulation, we predicted that CD40L should be expressed on virtually all CD4+ cells in which the activated X chromosome contained an intact CD40L gene. Expression of CD40L among carriers ranged from 37 to 69% of CD4+ lymphocytes (Fig. 2Go), reflecting the random degree of inactivation of X chromosomes expressing either normal or mutated CD40L. The significant proportion of CD4+ lymphocytes that failed to express CD40L indicates that the absence of functional CD40L does not impair T cell maturation and release into the peripheral circulation.



View larger version (32K):
[in this window]
[in a new window]
  		FIGURE 2. CD40L expression by normal and by CD40L-deficient CD4+ T cells in XHIM carriers. Purified CD4+ T cells from an immunologically normal control and from XHIM carriers were stimulated with PMA (20 ng/ml) and ionomycin (1.5 µM) for 6 h before staining with FITC-conjugated anti-CD40L mAb and analysis by flow cytometry. Histograms demonstrate background isotype-control staining (shaded histogram) and CD40L staining (filled histogram). The percentage of cells expressing CD40L is indicated on each histogram.

 
CD40L-expressing CD4+ T cells have a partial advantage in CD45RO expression

To determine whether functional CD40L conveys an advantage in T cell Ag priming, we assayed the levels of coexpression of CD40L and CD45RO, a marker of Ag-primed lymphocytes (Fig. 3GoA and Table IIGo). CD4+ T cells were isolated from XHIM carriers, stimulated with PMA and ionomycin, and analyzed by two-color flow cytometry for coexpression of CD40L and CD45RO. Analysis of the level of coexpression of CD40L and CD45RO revealed that among the CD45RO population, a marginal majority expressed normal CD40L (Table IIGo), dictating that nearly one-half of the primed CD45RO-positive T cell population in XHIM carriers were CD40L-nonexpressing T cells. The degree of advantage for CD40L-expressing cells to become primed was calculated as the ratio of the percentage of CD40L-positive among all primed (CD45RO-positive) T cells to the percentage of CD40L-positive cells in the whole CD4+ population. The range of this ratio was between 1 and 2 in all of the carriers, indicating a marginal advantage for CD40L-expressing T cells in attaining a primed phenotype. However, CD40L+ T cells from carriers with a higher level of normal CD40L expression (e.g., carriers 3, 4, and 5) showed a relatively smaller advantage in attaining CD45RO expression than those from carriers with lower levels of normal CD40L expression (e.g., carriers 1 and 2). Nevertheless, these data demonstrated that T cells that failed to express CD40L were in fact able to become primed in a magnitude nearly that of CD40L-expressing T cells.



View larger version (47K):
[in this window]
[in a new window]
  		FIGURE 3. CD45RO (A) and CD45RA (B) isoform expression by normal and by CD40L-deficient CD4+ T cells in XHIM carriers. Purified CD4+ T cells from an immunologically normal control and from XHIM carriers were stimulated with PMA (20 ng/ml) and ionomycin (1.5 µM) for 6 h before staining with FITC-conjugated anti-CD45RO mAb and PE-conjugated anti-CD40L mAb and subsequent analysis by two-color flow cytometry. Density plots display mean fluorescence of CD40L staining on the y-axis and of CD45RO or CD45RA staining on the x-axis. The percentage of cells in each quadrant of interest is indicated in each plot.

 

View this table:
[in this window]
[in a new window]
  		Table II. Expression of CD40L among CD45RO+ and CD45RA+ T cells

 
CD40L-expressing CD4+ T cells constitute a minority of the naive T cell population

We further sought to determine whether the advantage that CD40L conveyed for becoming primed correlated with a lower likelihood of CD40L-positive lymphocytes to remain naive, as assessed by expression of the CD45RA isoform of CD45. By an analysis similar to that used for CD45RO coexpression, it was evident that CD40L-bearing T cells were at a relative disadvantage for remaining CD45RA positive (Fig. 3GoB and Table IIGo). However, this relative disadvantage was minor, with a ratio in all carriers of just under one.

CD40L-expressing cells have a minor advantage in cytokine production

We sought to test the primed status of CD40L-positive and -negative T cells functionally by using intracellular cytokine staining to assess their ability to make IL-2, as well as TNF-{alpha} and IFN-{gamma}, which reflects prior Ag priming, Th1 differentiation, and commitment to memory cell phenotype (25, 28). CD40L-expressing cells had little or no advantage over CD40L-negative cells in three of four carriers tested (Fig. 4Go and Table IIIGo). Only in carrier 1, whose CD40L expression was the lowest, did CD40L-positive T cells demonstrate a clear advantage in production of TNF-{alpha} and IFN-{gamma} and a smaller advantage in IL-2 production. However, in the other carriers, CD40L-deficient T cells showed little if any impairment in the ability to produce cytokines that characterize primed Th1 lymphocytes. Although the differences were small, T cells from carriers with higher levels of normal CD40L expression (e.g., carriers 3 and 4) had less of an advantage in cytokine production than those from carriers with lower levels of normal CD40L expression (e.g., carriers 1 and 2).



View larger version (62K):
[in this window]
[in a new window]
  		FIGURE 4. Cytokine expression by normal and by CD40L-deficient CD4+ T cells in XHIM carriers. Purified CD4+ T cells from XHIM carriers were stimulated with PMA (20 ng/ml) and ionomycin (1.5 µM) for 6 h, with addition of monensin (2 µM) for the final 2 h of stimulation. The cells were stained with PE-conjugated anti-CD40L mAb, fixed with 2% paraformaldehyde, and made permeable by 1% saponin for intracellular cytokine staining with FITC-conjugated mAbs directed against the indicated cytokines. They then were subjected to subsequent analysis by two-color flow cytometry. Density plots display mean fluorescence of CD40L staining on the y-axis and of staining for IFN-{gamma}, TNF-{alpha}, or IL-2 on the x-axis.

 

View this table:
[in this window]
[in a new window]
  		Table III. Expression of CD40L among IFN-{gamma}, TNF-{alpha}, and IL-2-producing T cells1

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Numerous studies, both in human patients with XHIM and in mouse models of CD40L deficiency, have demonstrated the importance of CD40L for T cell function. In these models, CD40L-mediated signaling is completely absent. However, the lack of evidence of immune deficiency in the maternal carriers of XHIM indicates that partial expression of CD40L among CD4+ T cells is adequate for protective immunity (24). It is possible that the CD40L-expressing population provides all of the effective T cell immunity in XHIM carriers, with no help from the CD40L-deficient fraction. This is supported by the observation that XHIM carriers with extreme lyonization of the X chromosome, resulting in only 5% of T cells expressing functional CD40L, can present with an XHIM phenotype (29). This would be consistent with the notion that CD40L itself acts as a costimulatory molecule for T cells, providing help only to cells that express it. An alternate possibility is that the support that CD40L provides for T cell immunity is a factor that can be shared by CD40L-deficient T cells, allowing both populations to contribute to T cell immunity. The observation that B7 molecules can reverse the T cell dysfunction in CD40L-deficient mice (6) would be in accord with this model in which B7 costimulation allows CD40L-deficient T cells to function as full effectors.

In this study, we have found that CD40L-deficient T cells in carriers of XHIM are minimally impaired in comparison with CD40L-expressing T cells in several parameters of T cell priming. This stands in contrast with the findings of deficient T cell priming in complete CD40L-deficient states both in human patients with XHIM (2) and in CD40L-deficient mice (4). However, our findings suggest that the presence in carriers of a fraction of T cells expressing CD40L can allow CD40L-deficient T cells to become primed T cells. It is not clear whether these primed CD40L-deficient T cells are operative in host defense in a manner that is truly equal to CD40L-expressing T cells. However, the observation that they can make TNF-{alpha} and IFN-{gamma} with a capacity near that of CD40L-expressing cells suggests that they are mediating T cell immunity.

The best reconciliation of these data with the T cell impairments found in complete CD40L deficiency states would be a model in which CD40L-deficient T cells can share the support provided by CD40L-expressing cells. Our observation that the relative advantage for CD40L+ cells decreases in carriers with higher levels of normal CD40L expression argues for a "bystander effect" that can be shared in a dose-dependent manner. This model is consistent with the induction of B7 or other downstream costimulatory molecules as the major mechanism of CD40L support of T cell immunity, rather than CD40L acting as a costimulatory molecule for T cells that express it. However, in contrast to the study of Uronen et al. (3), our study shows a marginal but consistent advantage for CD40L-expressing T cells in becoming primed. This may reflect the contribution of intracellular signaling by CD40L in T cell priming.

These findings also provide important information for the design of therapeutic strategies for the reconstitution of CD40L expression by stem cell transplantation or gene therapy. The apparent ability of CD40L-expressing cells to support the function of CD40L-deficient cells suggests that the efficiency of correction need not be higher than the level of CD40L expression found in XHIM carriers. Because most proposed methods of gene therapy achieve far less than 100% efficiency in gene correction, our study provides hope that such strategies may achieve a satisfactory outcome. Similarly, stem cell transplantation protocols that use nonmyeloablative conditioning regimes that may result in mixed hematopoietic chimerism would be expected to satisfactorily reconstitute CD40L-dependent helper T cell functions provided that the degree of chimerism for CD40L expression is comparable with that observed in XHIM carriers.


   Footnotes
 
1 This research was supported by U.S. Public Health Grant 1R29AI40534 (to R.L.F.), by a grant from the Charles Hood Foundation (to R.L.F.), by a Mentored Clinical Scientist Development Award (1K08AI01554-02) from the National Institute of Allergy and Infectious Disease, National Institutes of Health (to F.M.L.), and by a Research Grant from the American Cancer Society, Illinois Division (to P.R.S.). Back

2 Address correspondence and reprint requests to Dr. Francis M. Lobo, Department of Internal Medicine, Yale Child Health Research Center and Sections of Immunology, Yale University School of Medicine, 904 LCI, P.O. Box 208013, New Haven, CT 06520-8013. E-mail address: francis.lobo{at}yale.edu Back

3 Abbreviations used in this paper: CD40L, CD40 ligand; XHIM, X-linked hyper-IgM syndrome. Back

Received for publication July 6, 2001. Accepted for publication November 19, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Fuleihan, R. L.. 1998. The X-linked hyperimmunoglobulin M syndrome. Semin. Hematol. 35:321.[Medline]
  2. Jain, A., T. P. Atkinson, P. E. Lipsky, J. E. Slater, D. L. Nelson, W. Strober. 1999. Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome. J. Clin. Invest. 103:1151.[Medline]
  3. Uronen, H., R. E. Callard. 2000. Absence of CD40-CD40 ligand interactions in X-linked hyper-IgM syndrome does not affect differentiation of T helper cell subsets. Clin. Exp. Immunol. 121:346.[Medline]
  4. Grewal, I. S., J. Xu, R. A. Flavell. 1995. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature 378:617.[Medline]
  5. Noelle, R. J., T. Foy, M. Mackey, J. Budlmann. 1996. The role of CD40 and its ligand in peripheral T cell tolerance. J. Banchereau, and D. Dodet, and R. Schwartz, and E. Trannoy, eds. Immune Tolerance 135. Elsevier, Paris.
  6. Grewal, I. S., H. G. Foellmer, K. D. Grewal, J. Xu, F. Hardardottir, J. L. Baron, C. A. Janeway, R. A. Flavell. 1996. Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science 273:1864.[Abstract/Free Full Text]
  7. Wiley, J. A., A. G. Harmsen. 1995. CD40 ligand is required for resolution of Pneumocystis carinii pneumonia in mice. J. Immunol. 155:3525.[Abstract]
  8. Durie, F. H., A. Aruffo, J. Ledbetter, K. M. Crassi, W. R. Green, L. D. Fast, R. J. Noelle. 1994. Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. J. Clin. Invest. 94:1333.
  9. Li, Y., X. C. Li, X. X. Zheng, A. D. Wells, L. A. Turka, T. B. Strom. 1999. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat. Med. 5:1298.[Medline]
  10. Larsen, C. P., D. Z. Alexander, D. Hollenbach, E. T. Elwood, S. C. Ritchie, A. Aruffo, R. Hendrix, T. C. Pearson. 1996. CD40-gp39 interactions play a critical role during allograft rejections. Transplantation 61:4.[Medline]
  11. Durie, F. H., R. A. Fava, T. M. Foy, A. Aruffo, J. A. Ledbetter, R. J. Noelle. 1993. Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40. Science 261:1328.[Abstract/Free Full Text]
  12. Early, G. S., W. Zhao, C. M. Burns. 1996. Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice: response correlates with the absence of an anti-antibody response. J. Immunol. 157:3159.[Abstract]
  13. Ranhein, E. A., T. J. Kipps. 1993. Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J. Exp. Med. 180:925.[Abstract/Free Full Text]
  14. Caux, C., C. Massacrier, B. Vanbervliet, B. Dubois, C. Van Kooten, I. Durand, J. Banchereau. 1994. Activation of human dendritic cells through CD40 cross-linking. J. Exp. Med. 180:1263.[Abstract/Free Full Text]
  15. Kiener, P. A., D. P. Moran, B. M. Rankin, A. F. Wahl, A. Aruffo, D. Hollenbaugh. 1995. Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J. Immunol. 155:4917.[Abstract]
  16. Harding, F. A., J. G. McArthur, J. A. Gross, D. H. Raulet, J. P. Allison. 1992. CD28-mediated signaling co-stimulates murine T cells and prevents induction of anergy in T cell clones. Nature 356:607.[Medline]
  17. Hollander, G. A., E. Castigli, R. Kulbacki, M. Su, S. J. Burakoff, J. C. Gutierrez-Ramos, R. S. Geha. 1996. Induction of alloantigen-specific tolerance by B cells from CD40-deficient mice. Proc. Natl. Acad. Sci. USA 93:4994.[Abstract/Free Full Text]
  18. Cella, M., D. Scheidegger, K. Palmer-Lehman, P. Lane, A. Lanzavecchia, G. Alber. 1996. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J. Exp. Med. 184:747.[Abstract/Free Full Text]
  19. Brenner, B., U. Koppenhoefer, H. Grassme, J. Kun, F. Lang, E. Gulbins. 1997. Evidence for a novel function for the CD40L as a signaling molecule in T lymphocytes. FEBS Lett. 417:301.[Medline]
  20. Brenner, B., U. Koppenhoefer, A. Lepple-Wienhues, H. Grassme, C. Muller, C. P. Speer, F. Lang, E. Gulbins. 1997. The CD40 ligand directly activates T lymphocytes via tyrosine phosphorylation dependent PKC activation. Biochem. Biophys. Res. Commun. 239:11.[Medline]
  21. Koppenhoefer, U., B. Brenner, F. Lang, E. Gulbins. 1997. The CD40-ligand stimulates T-lymphocytes via the neutral sphingomyelinase: a novel function of the CD40-ligand as signaling molecule. FEBS Lett. 414:444.[Medline]
  22. van Essen, D., H. Kikutani, D. Gray. 1995. CD40 ligand-transduced co-stimulation of T cells in the development of helper function. Nature 378:620.[Medline]
  23. Poudrier, J., D. van Essen, S. Morales-Alcelay, T. Leanderson, S. Bergthorsdottir, D. Gray. 1998. CD40 ligand signals optimize T helper cell cytokine production: role in Th2 development and induction of germinal centers. Eur. J. Immunol. 28:3371.[Medline]
  24. Hollenbaugh, D., L. H. Wu, H. D. Ochs, S. Nonoyama, L. S. Grosmaire, J. A. Ledbetter, R. J. Noelle, H. Hill, A. Aruffo. 1994. The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIGM1. J. Clin. Invest. 94:616.
  25. Picker, L. J., M. K. Singh, Z. Zdraveski, J. R. Treer, S. L. Waldorp. 1995. Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood 86:1408.[Abstract/Free Full Text]
  26. Fuleihan, R., N. Ramesh, R. Loh, H. Jabara, R. S. Rosen, T. Chatila, S. M. Fu, I. Stamenkovic, R. S. Geha. 1993. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc. Natl. Acad. Sci. USA 90:2170.[Abstract/Free Full Text]
  27. Lobo, F. M., E. A. Cooper, R. L. Fuleihan. 1997. Of mice and men: CD40 ligand is not required for T cell priming in humans. J. Allergy Clin. Immunol. 99:S398.
  28. Constant, S. L., K. Bottomly. 1997. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu. Rev. Immunol. 15:297.[Medline]
  29. de Saint Basile, G., M. Tabone, A. Durandy, F. Phan, A. Fischer, F. Le Deist. 1999. CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization. Eur. J. Immunol. 29:367.[Medline]



This article has been cited by other articles:


Home page
 BloodHome page
S. Fontana, D. Moratto, S. Mangal, M. De Francesco, W. Vermi, S. Ferrari, F. Facchetti, N. Kutukculer, C. Fiorini, M. Duse, et al.
Functional defects of dendritic cells in patients with CD40 deficiency
Blood, December 1, 2003; 102(12): 4099 - 4106.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lobo, F. M.
Right arrow Articles by Fuleihan, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lobo, F. M.
Right arrow Articles by Fuleihan, R. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS