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Observation |

Monoclonal T-Cell Dyscrasia of Undetermined Significance Associated With Recalcitrant Erythroderma FREE

Robert Gniadecki, MD, PhD, DSc; Ansgar Lukowsky, PhD
[+] Author Affiliations

Author Affiliations: Departments of Dermatology, Bispebjerg Hospital, University of Copenhagen, Denmark (Dr Gniadecki) and Charité Hospital, Berlin, Germany (Dr Lukowsky).


Arch Dermatol. 2005;141(3):361-367. doi:10.1001/archpedi.161.4.356.
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Published online

ABSTRACT

Background  Erythroderma is a diffuse, inflammatory skin reaction that, in rare instances, is associated with hematologic maligancies such as cutaneous T-cell lymphoma (erythrodermic mycosis fungoides) or T-cell leukemia (Sézary syndrome or adult T-cell leukemia/lymphoma).

Observations  We screened 30 patients with erythroderma (20 patients with erythroderma of known etiology and 10 patients with idiopathic erythroderma) for the presence of circulating monoclonal T-lymphocyte populations using T-cell receptor (TCR)–γ gene–specific polymerase chain reaction and automated capillary DNA electrophoresis. Moreover, the phenotypic analysis of peripheral blood CD4+ lymphocytes was performed using the following surface markers: CD3, CD7, CD8, CD25, CD26, CD27, CD28, CD29, CD30, CD45RO, CD45RA, CD56, CD134, HLA-DR, TCRαβ, TCRγδ, and cutaneous lymphocyte antigen (CLA). In 5 patients with idiopathic erythroderma we detected T-cell clones in peripheral blood (in 1 case, associated with the presence of the same clone in the skin) and a 2-fold increase in the proportion of CD3+CD4+CD7CD26 cells. Cell depletion studies indicated that the monoclonal T cells were present within the CD4+CD7 cell population. Clinically, all patients had chronic, recalcitrant erythroderma but none developed any hematological malignancy during their lifetimes or fulfilled the criteria for cutaneous lymphoma or Sézary syndrome.

Conclusions  A proportion of patients with chronic erythroderma present with the monoclonal expansion of CD4+CD7CD26 lymphocytes in their blood. This condition represents a probably benign T-cell dyscrasia, or one of very low malignancy. Alongside monoclonal gammapathy of undetermined significance (MGUS) and monoclonal (B-cell) lymphocytosis of undetermined significance (MLUS), we propose using monoclonal T-cell dyscrasia of undetermined significance (MTUS) to underline a conceptual similarity between this disorder and the more common types of lymphocytic dyscrasia.

Figures in this Article

Erythroderma is an extensive inflammatory skin reaction affecting more than 90% of the body surface. The condition is rare, with an incidence of approximately 1 per 100 000 polulation,1 and its etiology is variable. Eczemas, psoriasis, and drug reactions are the most frequent causes of erythroderma. In 15% to30% of cases the cause cannot be found (idiopathic erythroderma),1,2 and up to 40% of these run a chronic course not manageable by local or systemic therapies (chronic idiopathic erythroderma or “red man” syndrome).3,4

The possible association between chronic erythroderma and cutaneous T-cell lymphoma (CTCL) has long been recognized. Only a small proportion (5%-10%) of patients with chronic erythroderma develop clinically unequivocal mycosis fungoides or Sézary syndrome.1,35 However, some researchers believe that chronic erythroderma, eg, erythrodermic atopic dermatitis, is a preneoplastic condition.69 This concept has been promoted by Winkelmann and coworkers6,10,11 who coined the term pre-Sézary syndrome. This syndrome is defined as chronic erythroderma resembling that seen in Sézary syndrome, a Sézary cell count less than 109/mL, and a high risk of progression into frank leukemia (Sézary syndrome). Other features are palmoplantar keratoderma, alopecia, onychodystrophy, lymphadenopathy, and an increased level of circulating IgE. However, because none of these symptoms has been found consistently in all patients, pre-Sézary syndrome is difficult to separate from pseudo–CTCL erythrodermas such as adult-onset atopic dermatitis or Ofuji papuloerythroderma.5 For this reason the concept of pre-Sézary syndrome has not been universally accepted.

Molecular biology and flow cytometry techniques that enable sensitive detection and characterization of clonal expansion of T cells have been used for more than a decade for the diagnosis of leukemias and lymphomas, including cutaneous lymphomas.12 A T-cell population with monoclonally rearranged T-cell receptor (TCR) genes is readily detectable in peripheral blood in Sézary syndrome. Patients with Sézary syndrome also have an increased proportion of circulating CD4+CD7 and CD26 cells,5 but it is still unclear whether these represent a malignant population or merely reactive lymphocytes.1316 CD4+7 are also detectable in late stages of mycosis fungoides with or without erythroderma, and they might be used for monitoring response to therapy.17,18

In view of these reports suggesting the diagnostic value of flow cytometry and TCR gene rearrangement for CTCL we have included these studies in the standard diagnostic workup of patients with erythroderma since 1999. We were able to identify a group of patients with chronic, recalcitrant erythroderma accompanied by a monoclonal expansion of CD4+72629+ T lymphocytes. These patients fulfilled the criteria for pre-Sézary syndrome but none developed CTCL during the 4-year observation period. We propose that the clinical syndrome described herein represents a T-cell variant within the group of monoclonal hematologic dyscrasias with a yet undetermined risk of progression to malignancy.

METHODS

PATIENTS

A total of 30 patients, 7 women and 23 men aged between 29 and 90 years seen in our department during a 3-year period were included. Of 5 more patients with erythroderma, 3 died or were lost to follow-up before immunophenotyping and 2 did not receive peripheral blood immunophenotyping because the attending physician did not order the study. Patient distribution and diagnoses are shown in Figure 1. Six of the 10 patients with idiopathic erythroderma had chronic, recalcitrant disease defined as symptoms persisting for more than 6 months without any response to local and systemic glucocorticoid treatment. The other 4 patients experienced a single episode of erythroderma (n = 2) or relapsing disease between periods with no or minimal skin symptoms (n = 2). For control purposes (control of CD7 antibody and TCR-γ rearrangement sensitivity) blood from 6 patients with Sézary syndrome were included (the samples were provided by Mark Pittelkow, MD, Mayo Clinic, Rochester, Minn). For all patients, a minimum workup included hematologic and blood chemistry studies, 4-mm skin punch biopsy specimens for histologic studies, a chest radiograph, and abdominal ultrasonographic screening for occult tumors.

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Figure 1.

Characteristics of the patients with erythroderma included in this study.

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PERIPHERAL BLOOD IMMUNOPHENOTYPING

Venous blood was collected in EDTA Vacutainer tubes (Becton, Dickinson and Co, Franklin Lakes, NJ) and processed immediately. One milliliter of blood was lysed for 5 minutes at 37°C with 50 mL of lysis buffer (0.83% ammonium chloride, 0.1% kalium bicarbonate, and 0.004% EDTA) and the leukocytes were washed once in phosphate-buffered saline (PBS) solution. The cells were counted manually and resuspended in PBS solution for a concentration of 2.4 × 106/mL. Antibody staining for immunophenotyping by laser scanning cytometry was performed according to the method published by Clatch and colleagues,19-22 with slight modifications. Briefly, 3 μL of the fluorescein isothiocyanate (FITC)–, phycoerythrin (PE)-, and phycoerythrin cyanogen 5 (PECy5)–labeled antibodies (Table 1) was added to 20 μL of cell suspension and the mixture was gently pipetted onto custom-made chamber slides assembled on standard microscope glass slides. The following antibody-labeling reactions were performed: (1) CD45,CD4,CD8; (2) CD3,CD4, CLA; (3) CD4, HLA-DR, CD134; (4) CD4, CD45RO, CD45RA; (5) CD4, CD25, CD56; (6) CD4, CD7, CD26; (7) CD4, CD7, CD27; (8) CD4, CD7, CD28; (9) CD4, CD7, CD29; (10) CD4, CD7, CD30; (11) CD4, TCRαβ, TCRγδ; and (12) isotype controls. After a 30-minute incubation at 4°C the cells were washed with PBS and scanned in a laser scanning cytometer (CompuCyte, Cambridge, Mass) using the 488-nm line of argon laser as an excitation source. Integrated fluorescence in the green (FITC), orange (RPE) and far red (PC5) channels were collected on a cell-to-cell basis and presented as dot-plot diagrams following off-line fluorescence compensation with the CompuCyte software. After scanning, the chamber slides were disassembled and the cells adhering to the bottom slide were fixed briefly in methanol, air-dried, and stained with Wright-Giemsa. The slides with stained cells were repositioned in the laser scanning cytometer and the cells with the required characteristics were re-found for visual inspection.

Table Graphic Jump LocationTable 1. List of Antibodies Used for T-Cell Immunophenotyping
TCR -γ GENE REARRANGEMENT STUDIES

Skin biopsy specimens (4-mm punch) and mononuclear blood cells purified on Ficoll were analyzed by means of a polymerase chain reaction with fluorescence fragment product analysis using an automated capillary electrophoresis DNA sequencer (GeneScan; Applied Biosystems, Foster City, Calif), as described elsewhere in detail.2325 For lymphocyte depletion/enrichment the peripheral leukocytes were prepared by ammonium chloride lysis, as described above, and washed twice in PBS. CD4+ cells were positively isolated or selectively depleted using a Dynabeads M-450 CD4 kit (Dynal Biotech, Oslo, Norway) according to the protocol supplied by the manufacturer. For CD7 depletion, 150 μL of CD7 antibody (Dako Corp, Glostrup, Denmark) was added to 107 peripheral leukocytes (total volume, 1 mL) and the cells were incubated at 4°C for 30 minutes. After washing, the cells were resuspended in 80 μL of PBS solution and 20 μL of goat anti-mouse antibodies linked to Dynabeads M-450 magnetic beads (Dynal Biotech) was added. After a 20-minute incubation at 4°C the cells were washed and resuspended in 500 μL of PBS in an Eppendorf tube and mounted on a magnetic device (Dynal). The supernatant was collected as the negative fraction. The next two 500-μL washes were discarded, and the remaining cells constituted the positive fraction. To check for the purity of the separated fractions the CD4- and CD7-depleted cells were stained for tricolor laser scanning cytometry with the following: (1) CD3-RPE + CD4-PECy5 + CD8-FITC; (2) CD3-RPE + CD4-PECy5 + CD7-FITC; and (3) CD3-RPE + CD4-PECy5 + CD26-FITC. In 2 of 4 cases it was technically feasible to deplete more than 95% of CD4+ or CD7+ cells.

RESULTS

PATIENTS WITH ERYTHRODERMA, PERIPHERAL CD3+CD4+CD7CD26 CELL EXPANSION, AND MONOCLONAL T-CELL DYSCRASIA

Peripheral blood immunophenotypic studies were performed using a broad panel of antibodies (Table 1) to determine the CD4/CD8 cell ratio and subpopulations of CD3+4+ lymphocytes according to the expression of different surface markers. Among the 30 patients included in this study, we found 5 patients (apart from 1 patient with clinically obvious Sézary syndrome) who presented with a more than 2-fold enrichment in the ratio of CD3+CD4+CD7CD26/CD3+CD4+ lymphocyte subpopulations (Table 2, Figure 2, and Figure 3). Since the presence of CD4+CD7 lymphocytes could signify the development of Sézary syndrome, we performed the TCR clonality studies. In all 5 patients we found a monoclonal population of lymphocytes by detecting a clonally rearranged TCR-γ receptor chain. In the other 4 patients only a blood sample gave this result, but in patient 5 both blood and skin samples showed identical rearrangements. None of these patients, however, showed blood or bone marrow characteristics of leukemic involvement (summary characteristics are provided in Table 2). They did not have palpable lymph nodes except patient 3, in whom findings from excisional biopsy of the left inguinal node showed reactive dermopathic changes. A slight eosinophilia and an increase in total IgE concentration were noted in most patients. Peripheral blood smears showed normal numbers of Sézary cells. Biopsy specimens from all patients showed predominantly lymphocytic, superficial perivascular infiltrates without exocytosis or epidermotropism, with slight to moderate parakeratosis and spongiosis. Their clinical course was protracted, as they were resistant to treatments that included topical and systemic glucocorticoids, systemic retinoids (acitretin), psoralen–UV-A, and methotrexate. In the case of patient 1, however, a temporary improvement was noted after he received a weekly dose of 25 mg of methotrexate, and the clinical response correlated with a decrease in the proportion of CD4+CD7 cells from 69% to 31%. However, his erythroderma relapsed 4 months later despite the treatment, and his CD4+CD7 cell count increased to 71%. None of these 5 patients developed unequivocal Sézary syndrome as defined by the clinical or hematologic criteria,5 or any other kind of malignancy during their lifetime. All died within 4 years after diagnosis of causes unrelated to erythroderma (2 of ischemic heart disease, 1 of stroke, and 1 of unknown cause).

Place holder to copy figure label and caption
Figure 2.

Typical erythroderma (bright red with slight scaling) in a patient with monoclonal T−cell dyscrasia of undetermined significance (MTUS) (patient 1).

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Figure 3.

Phenotypic characteristics of peripheral blood CD3+CD4+ lymphocytes in healthy individuals, patients with monoclonal T−cell dyscrasia of undetermined significance (MTUS), and patients with erythroderma of other etiology. A, Proportion of CD4+CD7 cells as a function of age, with regression line and 95% prediction interval. B, Examples of laser scanning cytometry results of peripheral blood lymphocytes in a patient with erythroderma (control), patient 1 with MTUS, and a patient with Sézary syndrome. In Sézary syndrome CD4+CD7 cells have a 2− to 3−fold reduced CD7 expression compared with CD4+CD7 cells in patients with MTUS. FITC indicates fluorescein isothiocyanate.

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Table Graphic Jump LocationTable 2. Characteristics of the Patients With Monoclonal T-Cell Dyscrasia of Undetermined Significance (MTUS)
FURTHER CHARACTERISTICS OF CD3+CD4+CD7CD26 CELLS

The phenotypic characteristics of CD4+CD7CD26 cells were the following: CD3+, CD8, CD25, CD27+/−, CD28+, CD29+, CD30, CD45RO+, CD45RA, CD56, CD134, HLA-DR, CLA, TCRαβ+, and TCRγδ, ie, they corresponded to the phenotype of resting memory CD4+ cells. To investigate the possibility that the subpopulation of monoclonal T cells resided within the expanded CD4+CD7CD26 compartment, we repeated the TCRγ rearrangement studies on peripheral blood cells depleted of monoclonal CD4 and CD7 antibodies. In 2 cases (patients 1 and 3) we succeeded in obtaining pure populations containing less than 4% of CD4+ cells (CD4 antibody depletion) or CD7 cells (CD7 antibody depletion). In both patients the monoclonal TCRγ rearrangement was absent in the CD4-depleted cells but still detectable after CD7 depletion or in positively selected CD4+ cells.

We were also interested in investigating the morphologic characteristics of CD4+CD7 cells. To accomplish this task we took advantage of the laser scanning cytometry technique, which provides the possibility of finding cells with specific characteristics and observing their morphologic features under a light microscope. In each of the 4 described patients we observed 100 to 150 Wright-Giemsa–stained CD4+CD7 cells and found that only 6 to 17 cells could be classified as having Sézary cell morphology. Otherwise, the cells were small lymphocytes. This was not different from what can be found in the peripheral blood of healthy volunteers. In conclusion, our findings indicate that some of the CD4+CD7 cells are monoclonal but retain normal lymphocytic morphology.

COMMENT

Monoclonal expansions of lymphocytes occur occasionally in elderly individuals and comprise B-cell, T-cell, or plasma-cell dyscrasias. B-cell and plasma-cell dyscrasias are most common and can be detected in approximately 10% of healthy adults older than 80 years by the presence of a monoclonal immunoglobulin peak on serum electrophoresis. This condition, named monoclonal gammapathy of undetermined significance (MGUS) is considered to be preneoplastic since patients with MGUS have a severely increased risk for developing multiple myeloma and macroglobulinemia.26 Another type of B−cell dyscrasia is monoclonal B lymphocytosis of undetermined significance (MLUS), which is a clinically benign variant of chronic B−cell leukemia.27

Here we describe a subpopulation of elderly patients with idiopathic, chronic erythroderma with associated monoclonal dyscrasia of T cells (an abbreviation, MTUS, is proposed to be analogous with MGUS and MLUS). Monoclonal expansions of T cells are much less common that B−cell dyscrasias and their clinical relevance is poorly understood. CD8+ and CD4+ lymphocyte clones have been detected in elderly individuals28,29 and even in old mice.30 These monoclonal T cells have a variable phenotype; however, the most consistent finding is CD7CD45RO+, which resembles the phenotype seen in our patients with erythroderma.

Very little is known about the pathogenesis and clinical importance of monoclonal T−cell dyscrasias in elderly people. Some authors have suggested that they occur because of a transformational event analogous to the situation seen in MGUS, and it seems that at least in some cases (albeit rarely) clinically silent monoclonal T−cell dyscrasia progresses into malignancy.3133 If the same pathogenic scenario was true for our patients, erythroderma with monoclonal T−cell dyscrasia could correspond to the pre−Sézary syndrome.10 Some support to this speculative notion is provided by an obvious similarity with the known surface phenotype of the cells in Sézary syndrome or advanced mycosis fungoides.

A lack of CD7 and CD26 expression is by no means specific to Sézary cells. Reactive−memory T cells in benign inflammatory skin conditions, such as atopic dermatitis, psoriasis, or infections, often have the CD7CD26CD45RO+ phenotype.3436 According to this concept monoclonal T−cell populations represent reactive cells that were not eliminated by immunoregulatory processes. It is important to stress in this context that T−cell rearrangement studies do not allow differentiating whether the detected clone is a result of malignant tranformation or, rather, due to selection of reactive T lymphocytes. None of our patients with erythroderma and monoclonal T−cell dyscrasia fulfilled the criteria of Sézary syndrome; they all had Sézary cell counts below 5% or 1000/μL, did not develop lymphadenopathy, and their CD4/CD8 ratio was much lower than that normally seen in Sézary syndrome. The CD7 expression is much lower in Sézary syndrome than in MTUS (Figure 3B). Moreover, the CD4+CD7 cells in our patients did not have the Sézary cell morphology but mostly resembled normal small lymphocytes. None of the patients developed lymphoma or an other malignancy during the period of observation. Taken together, we cannot eliminate the possibility that observed monoclonal cells are non−neoplastic or alternatively represent an “abortive” dead−end transformation event.

Monoclonal CD4 and CD8 cells have repeatedly been found in different autoimmune and inflammatory diseases such as rheumatoid arthritis, atherosclerosis, chronic viral infections, and multiple sclerosis.3741 At least in patients with rheumatoid arthritis, there is ample evidence suggesting that monoclonal circulating CD4+CD7CD45RO+ cells escaped from peripheral tolerance and are autoreactive.40,42 The maintenance of these clones is supported by some cytokines43 and further enhanced by their resistance to apoptosis.44 It is conceivable that the monoclonal T−cell population in patients with erythroderma results from a chronic stimulation of the immune system with a yet unidentified cutaneous autoantigen. However, in contrast to the clones detected in rheumatoid arthritis40 and in healthy aging individuals,41,4447 which are approximately enriched 5−fold in CD28 cells, we did not find any differences in the proportion of CD4+28 cells between patients with monoclonal T−cell dyscrasia and those with a known cause of erythroderma (Table 2). This seems to be an important point since it has been argued that the loss of CD28 expression occurs specifically in senescent T cells,47 depends on the cytokine balance,48 and, most importantly, the CD4+28 cells may represent a functionally distinct cell type resembling the natural killer lymphocytes.48,49 If the T−cell clones detected by us in patients with erythrodermia represent inflammatory, possibly autoreactive T cells, their nature is probably different from that of CD4+CD7CD28 cells.

In summary, we describe an association between chronic idiopathic erythroderma with monoclonal T−cell dyscrasia in elderly patients (MTUS−E syndrome). It is likely that the presence of T−cell monoclonality and erythroderma are related since their association by chance is extremely improbable ( approximately 10−8, as the probability of having erythroderma is 10−5 and the probability of having T−cell dyscrasia is 10−3). Moreover, the case of patient 1, in whom the use of methotrexate provided a temporary alleviation of symptoms, with an associated decrease in the proportion of CD4+CD7CD26 cells, further underscores the possible causal relationships between erythroderma and T−cell dyscrasia. However, it remains unknown whether the detected monoclonal population of CD4+CD7CD26 cells represents (auto)reactive T−lymphocytes mediating the chronic inflammatory skin reaction (pseudo–CTCL erythroderma) or, rather, is a result of a transformation event (an abortive or very indolent form of erythrodermic CTCL).

ARTICLE INFORMATION

Correspondence: Robert Gniadecki, MD, DSc, Department of Dermatology D, Bispebjerg Hospital, Bispebjerg bakke 23, DK−2400 Copenhagen NV, Denmark (rg01@bbh.hosp.dk).

Accepted for Publication: July 23, 2004.

Funding/Support: This work was supported by grants from Aage Bangs Fond and the Haenschs Fund (Dr Gniadecki).

Acknowledgment: We thank Ingelise Pedersen for her skillful assistance with the laser scanning cytometry.

Financial Disclosure: None.

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Vallejo  ANWeyand  CMGoronzy  JJ T−cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection Trends Mol Med 2004;10119- 124
PubMed Link to Article
Warrington  KJTakemura  SGoronzy  JJWeyand  CM CD4+,CD28 T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems Arthritis Rheum 2001;4413- 20
PubMed Link to Article
Ku  CCKappler  JMarrack  P The growth of the very large CD8+ T cell clones in older mice is controlled by cytokines J Immunol 2001;1662186- 2193
PubMed Link to Article
Vallejo  ANSchirmer  MWeyand  CMGoronzy  JJ Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways J Immunol 2000;1656301- 6307
PubMed Link to Article
Vallejo  ANBrandes  JCWeyand  CMGoronzy  JJ Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence J Immunol 1999;1626572- 6579
PubMed
Vallejo  ANWeyand  CMGoronzy  JJ Functional disruption of the CD28 gene transcriptional initiator in senescent T cells J Biol Chem 2001;2762565- 2570
PubMed Link to Article
Vallejo  ANBryl  EKlarskov  KNaylor  SWeyand  CMGoronzy  JJ Molecular basis for the loss of CD28 expression in senescent T cells J Biol Chem 2002;27746940- 46949
PubMed Link to Article
Warrington  KJVallejo  ANWeyand  CMGoronzy  JJ CD28 loss in senescent CD4+ T cells: reversal by interleukin−12 stimulation Blood 2003;1013543- 3549
PubMed Link to Article
Snyder  MRMuegge  LOOfford  C  et al.  Formation of the killer Ig−like receptor repertoire on CD4+CD28null T cells J Immunol 2002;1683839- 3846
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Characteristics of the patients with erythroderma included in this study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Typical erythroderma (bright red with slight scaling) in a patient with monoclonal T−cell dyscrasia of undetermined significance (MTUS) (patient 1).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Phenotypic characteristics of peripheral blood CD3+CD4+ lymphocytes in healthy individuals, patients with monoclonal T−cell dyscrasia of undetermined significance (MTUS), and patients with erythroderma of other etiology. A, Proportion of CD4+CD7 cells as a function of age, with regression line and 95% prediction interval. B, Examples of laser scanning cytometry results of peripheral blood lymphocytes in a patient with erythroderma (control), patient 1 with MTUS, and a patient with Sézary syndrome. In Sézary syndrome CD4+CD7 cells have a 2− to 3−fold reduced CD7 expression compared with CD4+CD7 cells in patients with MTUS. FITC indicates fluorescein isothiocyanate.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. List of Antibodies Used for T-Cell Immunophenotyping
Table Graphic Jump LocationTable 2. Characteristics of the Patients With Monoclonal T-Cell Dyscrasia of Undetermined Significance (MTUS)

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PubMed Link to Article
Warrington  KJTakemura  SGoronzy  JJWeyand  CM CD4+,CD28 T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems Arthritis Rheum 2001;4413- 20
PubMed Link to Article
Ku  CCKappler  JMarrack  P The growth of the very large CD8+ T cell clones in older mice is controlled by cytokines J Immunol 2001;1662186- 2193
PubMed Link to Article
Vallejo  ANSchirmer  MWeyand  CMGoronzy  JJ Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways J Immunol 2000;1656301- 6307
PubMed Link to Article
Vallejo  ANBrandes  JCWeyand  CMGoronzy  JJ Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence J Immunol 1999;1626572- 6579
PubMed
Vallejo  ANWeyand  CMGoronzy  JJ Functional disruption of the CD28 gene transcriptional initiator in senescent T cells J Biol Chem 2001;2762565- 2570
PubMed Link to Article
Vallejo  ANBryl  EKlarskov  KNaylor  SWeyand  CMGoronzy  JJ Molecular basis for the loss of CD28 expression in senescent T cells J Biol Chem 2002;27746940- 46949
PubMed Link to Article
Warrington  KJVallejo  ANWeyand  CMGoronzy  JJ CD28 loss in senescent CD4+ T cells: reversal by interleukin−12 stimulation Blood 2003;1013543- 3549
PubMed Link to Article
Snyder  MRMuegge  LOOfford  C  et al.  Formation of the killer Ig−like receptor repertoire on CD4+CD28null T cells J Immunol 2002;1683839- 3846
PubMed Link to Article

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