Generation of CD28− cells from long-term-stimulated CD8+CD28+ T cells: a possible mechanism accounting for the increased number of CD8+CD28− T cells in HIV-1-infected patients

Fiorentini, Simona; Malacarne, Fabio; Ricotta, Doris; Licenziati, Stefano; Solis, A A; Ausenda, S.; Francesco, M De; Garrafa, Emirena; Simonini, Americo; Balsari, Andrea; Turano, A; Caruso, Arnaldo

doi:10.1002/jlb.65.5.641

Cited by 24 publications

(22 citation statements)

References 34 publications

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“…CD8 + CD28 − T lymphocytes are infrequent in cord blood, thymus and lymph UPN1 VB061 BV6S1 2 2 24 1 6 VB064 BV6S4 11 11 22 14 8 VB141 BV14S1 4 2 15 3 5 UPN2 VB041 BV4S1, BV4S2 3 7 20 1 2 VB131 BV13S1, BV13S8 3 22 27 2 5 UPN3 VB091 BV9S1, BV9S2 2 3 53 1 0 VB131 BV13S1, BV13S8 15 5 13 7 40 VB141 BV14S1 4 2 20 Moreover, it has been recently reported that CD8 + CD28 − T cells can be generated from chronically stimulated CD8 + CD28 + T cells. 21 These results support the hypothesis that the CD8 + CD28 − T cell clones arise from the CD8 + CD28 + T cell population. It has been reported that CD4 + CD28 − T cells are found rarely in healthy individuals younger than 40 years and aging is associated with clonal expansion of the CD4 + CD28 − T cell population.…”

Section: Discussionsupporting

confidence: 83%

“…Like CD8 + T lymphocytes, CD4 + T cells may be chronically stimulated by certain antigens present in the host and then downregulate the CD28 expression during clonal expansion. 21 Alternatively, CD4 + CD28 − T cells may be resistant to cell death and have a slow turnover. There is evidence for clonal expansion of CD4 + CD28 − T cells in rheumatoid arthritis patients, and resistance to apoptosis and elevated expression of Bcl-2 are responsible for clonal expansion of CD4 + CD28 − T cells.…”

Section: Discussionmentioning

confidence: 99%

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Oligoclonal expansion of CD4+CD28− T lymphocytes in recipients of allogeneic hematopoietic cell grafts and identification of the same T cell clones within both CD4+CD28+ and CD4+CD28− T cell subsets

Hirokawa

Horiuchi

Kawabata

et al. 2001

Bone Marrow Transplant

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Summary:Recipients of allogeneic bone marrow grafts have clonally expanded CD8 + CD28 − T lymphocytes during the early period after transplantation, which leads to skewing of T cell receptor (TCR) repertoires. Here, we have addressed the question of whether clonal expansion of CD28 − T cells is also observed in CD4 + T lymphocytes after human allogeneic hematopoietic cell transplantation. We found that the fraction of T cells lacking CD28 expression in the CD4 + subset was increased after transplantation, and expanded CD4 + CD28 − T lymphocytes carrying certain TCRBV subfamilies showed limited TCR diversity. In order to further study the ontogeny of CD4 + CD28 − T cells, we analyzed the complementarity-determining region 3 (CDR3) of the TCR-␤ chain of CD4 + CD28 + and CD4 + CD28 − cells. We identified the same T cell clones within both CD4 + CD28 − and CD4 + CD28 + T cell subsets. These results suggest that both subsets are phenotypic variants of the same T cell lineage. Bone Marrow Transplantation (2001) 27, 1095-1100. Keywords: TCR-␤; CDR3; clone; CD4; CD28The CD28 molecule is a disulfide-linked homodimer expressed on the surface of T cells and it binds to the natural ligand B7 family members, CD80/CD86, expressed on antigen-presenting cells, resulting in costimulation of T cell activation. 1 In humans, all thymocytes and the vast majority of peripheral blood T cells express CD28 at birth. An increase of the proportion of CD8 + T cells lacking CD28 expression has been demonstrated in the aged population, 2 HIV-infected individuals 3,4 and bone marrow transplant recipients. 5,6 In contrast, in healthy individuals, only a few percent of CD4 + T cells lack CD28, 3 and expansion of CD4 + CD28 − T cells is scarcely reported in rheumatoid arthritis patients. 7,8 Correspondence Loss of CD28 expression has recently been implicated in lymphocyte senescence. 9,10 We have previously reported the oligoclonal expansions of CD8 + CD28 − T lymphocytes in recipients of allogeneic bone marrow grafts and the demonstration of identical T cell clones within both CD8 + CD28 − and CD8 + CD28 + T cell subsets. 11 These results suggest that clonally expanded CD8 + CD28 − T cells after allogeneic hematopoietic cell transplantation (HCT) are derived from the CD8 + CD28 + T cell subset, presumably by an antigen-driven mechanism. In the present study, we have addressed the question of whether clonal expansion of CD4 + CD28 − T cells is also observed in recipients of allogeneic hematopoietic cell grafts and whether these cells are the descendents of CD4 + T cells expressing CD28. Materials and methods PatientsInformed consent was obtained from the patients before blood samples were collected. All the patients were conditioned with myeloablative chemoradiotherapy, mostly consisting of fractionated total body irradiation (12 Gy in six fractions) and cyclophosphamide (60 mg/kg/day for 2 days), followed by infusion of allogeneic marrow or blood stem cell grafts from HLA-matched donors. All the patients received cyclosporin A and short-term me...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Oligoclonal expansion of CD4+CD28− T lymphocytes in recipients of allogeneic hematopoietic cell grafts and identification of the same T cell clones within both CD4+CD28+ and CD4+CD28− T cell subsets

Hirokawa

Horiuchi

Kawabata

et al. 2001

Bone Marrow Transplant

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“…This result correlates well with preferential loss of CD28 expression on CD8 T cells, which could be mediated by the elucidated events at the CD28 promoter. 20,26 Moreover, our data for the first time demonstrate significant differences in CD28 regulation in response to short-term TCR-mediated activation in primary CD8 versus CD4 T cells.…”

Section: Selective Cell Division-linked Down-modulation Of Cd28 Surfamentioning

confidence: 58%

Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4 and CD8 subsets

Janković

Messaoudi

Nikolich‐Žugich

2003

Blood

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A prominent theory of immune senescence holds that repeated antigenic stimulation and decreased production of naive cells combine to progressively exhaust the reserve of lymphocytes available to fight new pathogens, culminating in an accumulation of lymphocytes that achieved replicative senescence. A well-defined primate model of immune senescence in vivo would greatly facilitate testing of this theory. Here, we investigated phenotypic and functional T-cell aging in the rhesus macaques (RMs), currently the dominant primate model of AIDS. Our results show that sharp differences exist between the CD8 and CD4 T-cell subsets in (1) cellcycle programs (as assessed by both in vitro proliferation and in vivo turnover measurement); (2) CD28 regulation on cell-cycle entry; and (3) accumulation of immediate effector cells among the CD28 ؊ cells, believed to be close to or at replicative senescence. These results further suggest poor reliability of CD28 as a marker for senescence. We suggest that some of the T-cell aging phenomenology in RMs can be ascribed to accentuation over time of the inherent differences in activation programs in CD8 and CD4 T cells. IntroductionDuring aging, the immune system undergoes dramatic changes in both structure and function. Macroscopically, the most evident event is the involution of the thymus, which heavily diminishes the production of naive T cells. Consequently, peripheral lymphocyte subset composition gets shifted toward the memory phenotype, as an increasing proportion of naive T cells become exposed to foreign antigens (Ag's) over time. T-cell-receptor (TCR) diversity of the aging memory T-cell population is also frequently restricted as homeostatic mechanisms that maintain diverse clonal composition of the T-cell repertoire progressively break down. [1][2][3] Findings suggest that this loss of T-cell homeostasis, reflected by a significant increase in CD8 T-cell numbers, an inverted CD4/CD8 ratio, and reduced T-cell diversity, 4-6 is associated with higher mortality in the aging human. 4 Indeed, clinical evidence clearly indicates the deterioration of T-cell immunity in the elderly. 1 Moreover, numerous studies have demonstrated impaired T-cell activation, and findings have precisely defined multiple defects in TCR-mediated signaling in senescent rodent T cells. [7][8][9][10] However, the mechanisms linking specific age-related changes in T-cell-subset distribution and function to the age-related immunodeficiency are still incompletely understood.Most of the existing data describing the age-related changes in T-cell function come from studies of the rodent immune system. Although these models have been invaluable in elucidating various fundamental facets of the immune system, including its (dys)regulation in aging, there are reminders that the results from rodent models do not automatically translate to humans. This lack of translation includes failure in humans of vaccine approaches that were validated in rodents. 11 Moreover, in the specific case of aging, there are additional o...

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“…28 Moreover, it has been recently Bone Marrow Transplantation reported that CD8 ϩ CD28 Ϫ T cells can be generated from chronically stimulated CD8 ϩ CD28 ϩ T cells. 29 Mugnaini et al 30 have also reported the presence of identical expanded clones within both CD8 ϩ CD28 Ϫ and CD8 ϩ CD28 ϩ T cell fractions in HIV patients. Thus, it has become more evident that CD8 ϩ CD28 Ϫ and CD8 ϩ CD28 ϩ T cell subsets belong to the same T cell lineage with just a distinct phenotype.…”

Section: Discussionmentioning

confidence: 95%

Identification of the T cell clones expanding within both CD8+CD28+ and CD8+CD28− T cell subsets in recipients of allogeneic hematopoietic cell grafts and its implication in post-transplant skewing of T cell receptor repertoire

Horiuchi

Hirokawa

Kawabata

et al. 2001

Bone Marrow Transplant

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Summary:We have previously reported that skewed repertoires of T cell receptor-␤ chain variable region (TCRBV) and TCR-␣ chain variable region (TCRAV) are observed at an early period after allogeneic hematopoietic cell transplantation. Furthermore, we found that T lymphocytes using TCRBV24S1 were increased in 28% of the recipients of allogeneic grafts and an increase of TCRBV24S1 usage was shown to result from clonal expansions. Interestingly, the arginine residue was frequently present at the 3Ј terminal of BV24S1 segment and was followed by an acidic amino acid residue within the CDR3 region. These results suggest that these clonally expanded T cells are not randomly selected, but are expanded by stimulation with specific antigens. This study was undertaken to elucidate the mechanisms of the posttransplant skewing of TCR repertoires. Since the CD8 ؉ CD28 ؊ CD57 ؉ T cell subset has been reported to expand in the peripheral blood of patients receiving allogeneic hematopoietic cell grafts, we examined the TCRAV and TCRBV repertoires of the CD8 ؉ CD28 ؊ T cell and CD8 ؉ CD28 ؉ T cell subsets, and also determined the clonality of both T cell populations. In all three recipients examined, the CD8 ؉ CD28 ؊ T cell subset appeared to define the post-transplant TCR repertoire of circulating blood T cells. Moreover, the CDR3 length of TCRBV imposed constraints in both CD8 ؉ CD28 ؊ T cell and CD8 ؉ CD28 ؉ T cell subsets. The DNA sequences of the CDR3 region were determined, and the same clones were identified within both CD8 ؉ CD28 ؊ and CD8 ؉ CD28 ؉ T cell subsets in the same individuals. These results suggest that the clonally expanded CD8 ؉ CD28 ؊ T cells after allogeneic hematopoietic cell transplantation derive from the CD8 ؉ CD28 ؉ T cell subset, possibly by an antigen-driven mechanism, resulting The CD28 molecule is a disulfide-linked homodimer expressed on the surface of T cells and binds to the natural ligand B7 family members, CD80/CD86, expressed on antigen-presenting cells, resulting in costimulation of T cell activation. 1 In humans, all thymocytes and the vast majority of peripheral blood T cells at birth express CD28. The proportion of CD8 ϩ T cells lacking CD28 expression increases during human aging, so that approximately 30% of CD8 ϩ T cells are negative for CD28 in adults. 2 Most of the CD8 ϩ CD28 Ϫ T cells express CD57. 2 A number of reports have shown that the proportion of CD8 ϩ CD28 Ϫ T cells is increased in HIV-infected patients. 3,4 The CD8 ϩ CD28 Ϫ CD57 ϩ T cell subset is also expanded in the peripheral blood of patients receiving allogeneic bone marrow transplants. 5,6 However, the mechanisms and biological relevance of this expansion remain to be elucidated. Moreover, it is still uncertain whether the CD8 ϩ CD28 Ϫ T cell subset arises from the CD8 ϩ CD28 ϩ T lymphocytes or whether both subsets belong to distinct T cell lineages.We have previously reported that the skewed TCRAV and TCRBV repertoires are observed at an early period after allogeneic hematopoietic cell transplantation. 7 We also fo...

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Generation of CD28− cells from long-term-stimulated CD8+CD28+ T cells: a possible mechanism accounting for the increased number of CD8+CD28− T cells in HIV-1-infected patients

Cited by 24 publications

References 34 publications

Oligoclonal expansion of CD4+CD28− T lymphocytes in recipients of allogeneic hematopoietic cell grafts and identification of the same T cell clones within both CD4+CD28+ and CD4+CD28− T cell subsets

Oligoclonal expansion of CD4+CD28− T lymphocytes in recipients of allogeneic hematopoietic cell grafts and identification of the same T cell clones within both CD4+CD28+ and CD4+CD28− T cell subsets

Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4 and CD8 subsets

Identification of the T cell clones expanding within both CD8+CD28+ and CD8+CD28− T cell subsets in recipients of allogeneic hematopoietic cell grafts and its implication in post-transplant skewing of T cell receptor repertoire

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