Phenotypic Heterogeneity of Persistent Expansions of CD4+CD8+ T Cells

Tonutti, Elio; Sala, Pierguido; Feruglio, Cristina; Yin, Zhinan; Colombatti, Alfonso

doi:10.1006/clin.1994.1204

Cited by 37 publications

(32 citation statements)

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“…Persistent expansions of CD4 1 CD8a 11 T cells in the peripheral blood are extremely rare (Tonutti et al, 1994). A minor subset (3-10%) of double-positive CD3 1 CD4 1 CD8a 1 intra-epithelial lymphocytes has been described in the small intestine of normal mice (Mosley et al, 1990;Lefrançois, 1991).…”

Section: Discussionmentioning

confidence: 99%

Identification of an enriched CD4+ CD8α++ CD8β+ T-cell subset among tumor-infiltrating lymphocytes in human renal cell carcinoma

et al. 1997

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Three-color immunofluorescence flow-cytometric analysis of freshly isolated tumor-infiltrating lymphocytes (TIL) from patients with primary renal cell carcinoma (RCC) revealed a unique, not previously described TIL subset with a CD3 1 CD4 1 CD8a 11 CD8b 1 phenotype. This subset represented at least 5% of CD3 1 TIL in 15 of 21 patients with clear cell RCC, whereas it was not or only marginally represented in patients with papillary RCC or sarcomatoid RCC. In one-third of the patients with clear cell RCC, more than 20% of CD3 1 TIL and in one patient more than half of the CD3 1 TIL displayed this phenotype. The occurrence of this subset was not associated with pathological stage, tumor diameter, nuclear grade, cytogenetic abnormalities or vascular invasion in this patient cohort. When present, the CD3 1 CD4 1 CD8a 11 CD8b 1 subset was detected in similar proportions in tumor tissue and tumor capsula, and it was also detected in adjacent non-tumoral renal tissue, albeit in much lower proportions. Despite strong cell surface expression of various activation markers (CD69, CD54 and HLA-DR), CD3 1 CD4 1 CD8a 11 CD8b 1 cells displayed no ex vivo cytolytic activity in an anti-CD3-redirected cytotoxicity assay. In contrast with CD3 1 CD4 1 CD8 2 cells from the same tumor sample, they were markedly deficient in IL-2Ra up-regulation following anti-CD3 triggering. The possibility that these cells represent either anergic cells or a highly specialized effector population with a discrete, as yet undescribed function is discussed. Int.

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Section: Discussionmentioning

confidence: 99%

Identification of an enriched CD4+ CD8α++ CD8β+ T-cell subset among tumor-infiltrating lymphocytes in human renal cell carcinoma

et al. 1997

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“…A proportion of cases with DP T cell expansions were reported to have the CD8␣␣ phenotype and a non-LGL morphology, 6 suggesting that DP ATLL cells may also be derived from certain activated peripheral T cells. On the other hand, three DP-ATLL cases are heterogeneous in the intensity of CD8␣␣ expression and expression of IL-4 mRNA.…”

Section: Tablementioning

confidence: 99%

“…2 Transient or persistent increases in DP-T cell numbers were recognized in patients with several diseases including viral infections and collagen diseases, and in apparently normal individuals. [3][4][5][6] DP T cell lymphocytosis appears to involve an increase in the number of activated peripheral T cells.…”

Section: Introductionmentioning

confidence: 99%

Phenotypical heterogeneity of CD4+CD8+ double-positive chronic T lymphoid leukemia

et al. 1998

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Chronic T lymphoid leukemias are defined as leukemias of post-thymic T cells. The CD4 ؉ CD8 ؉ double-positive (DP) phenotype is seen in a few cases. Since DP generally occurs in thymic T cells, whether the DP T leukemia cells represent thymic or peripheral T cells has been a matter of controversy. To address this issue, we studied phenotypical features in eight cases of DP T cell leukemia. Thymic DP T cells and peripheral CD8 ؉ T cells have CD8 of ␣␤ subunit, while CD8␣␣ is induced in CD4 ؉ T cells on activation with IL-4. We found that two patients with DP T large granular lymphocyte leukemia (LGLL) showed dim expression of CD8␣␣, identical to the phenotype on IL-4-activated DP-T cells. The leukemic cells of these patients expressed IL-4 mRNA and produced high levels of IL-4. These findings suggest that they may be derived from peripheral CD4 ؉ T cells. Three patients with adult T cell leukemia/lymphoma (ATLL) showed CD8␣␣, suggestive of an activated peripheral T cell origin. One case expressed CD8␣␣ dim and IL-4 mRNA, while the other two cases expressed no IL-4 mRNA and showed CD8␣␣ bright phenotype, features not found in normal T cell populations. Three patients with T-prolymphocytic leukemia (T-PLL) expressed CD8␣␤. The DP phenotype is relatively common in T-PLL, and CD4 + CD8␣␤ + is characteristic of thymic T cells. The DP T-PLL cells did not express TdT,CD1 or recombination activating gene-1 (RAG-1), which is down-regulated at the late stage of thymic T cell development. On the basis of these findings, we propose a late thymic origin for DP T-PLL. The phenotype of DP T cells differed for each entity and appeared to correlate with minor normal DP T cell population.

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“…These CD8 ϩ CD4 ϩ cells express higher levels of activation molecules than do costimulated CD8 ϩ T cells lacking CD4 expression (2,6). CD8 ϩ CD4 ϩ T cells constitute Ϸ3-5% of the human peripheral blood lymphocyte pool (7)(8)(9)(10). Certain conditions seem to influence CD8 ϩ CD4 ϩ cell levels in humans, including infection with HIV (11), human T lymphotrophic virus-1 (12), Epstein-Barr virus (8), human herpesvirus 6 (13), and aging (10).…”

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confidence: 99%

CD4 on CD8⁺T cells directly enhances effector function and is a target for HIV infection

Kitchen

Jones

LaForge

et al. 2004

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

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Costimulation of purified CD8 ؉ T lymphocytes induces de novo expression of CD4, suggesting a previously unrecognized function for this molecule in the immune response. Here, we report that the CD4 molecule plays a direct role in CD8 ؉ T cell function by modulating expression of IFN-␥ and Fas ligand, two important CD8 ؉ T cell effector molecules. CD4 expression also allows infection of CD8 cells by HIV, which results in down-regulation of the CD4 molecule and impairs the induction of IFN-␥, Fas ligand, and the cytotoxic responses of activated CD8 ؉ T cells. Thus, the CD4 molecule plays a direct role in CD8 T cell function, and infection of these cells by HIV provides an additional reservoir for the virus and also may contribute to the immunodeficiency seen in HIV disease. C D8 ϩ cytotoxic T lymphocytes (CTL) have a major role in antiviral immunity, directly killing virally infected cells and producing antiviral cytokines. Activation of these cells requires interaction of the T cell receptor complex with antigenic peptide and major histocompatibility complex (MHC) class I molecules on antigen-presenting cells (APCs) followed by a second costimulatory signal (1). After activation, there is a coordinated expression of various cell surface molecules, many of which play a direct role in cytotoxic activity. We and others have shown that costimulation of CD8 ϩ T cells from the peripheral blood results in the de novo expression of CD4, a molecule previously thought to be absent on this cell type at this stage of development (2-5). These CD8 ϩ CD4 ϩ cells express higher levels of activation molecules than do costimulated CD8 ϩ T cells lacking CD4 expression (2, 6). CD8 ϩ CD4 ϩ T cells constitute Ϸ3-5% of the human peripheral blood lymphocyte pool (7-10). Certain conditions seem to influence CD8 ϩ CD4 ϩ cell levels in humans, including infection with HIV (11), human T lymphotrophic virus-1 (12), Epstein-Barr virus (8), human herpesvirus 6 (13), and aging (10). CD8 ϩ CD4 ϩ cells also have been observed in monkeys (14-17), and in mice, rats, swine, and chickens (reviewed in ref. 18). In mice, CD8 ϩ CD4 ϩ cell levels increased after inoculation with reovirus or recombinant adenovirus (19,20). In each species, the CD8 ϩ CD4 ϩ populations usually displayed the phenotype of activated or previously activated T cells and, in the studies that assessed the composition of the CD8 dimer, were predominantly CD8␣␤ (versus CD8␣␣) cells (11,15,19). The presence of CD8 ϩ CD4 ϩ cells in normal individuals and the increased representation of these cells in individuals with disease or increased antigenic stimulation suggest a role for this cell type in immunity.The CD4 molecule has an important role in CD4 ϩ T helper (Th) cell development and response to antigen, including functioning as an adhesion molecule, regulating cellular activation and gene expression, and serving as a chemotactic receptor (21-23). Its role as the primary receptor for HIV is well known (24,25). The cytoplasmic tail of the CD4 molecule on Th cells is associated with t...

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Phenotypic Heterogeneity of Persistent Expansions of CD4+CD8+ T Cells

Cited by 37 publications

References 0 publications

Identification of an enriched CD4+ CD8α++ CD8β+ T-cell subset among tumor-infiltrating lymphocytes in human renal cell carcinoma

Identification of an enriched CD4+ CD8α++ CD8β+ T-cell subset among tumor-infiltrating lymphocytes in human renal cell carcinoma

Phenotypical heterogeneity of CD4+CD8+ double-positive chronic T lymphoid leukemia

CD4 on CD8⁺T cells directly enhances effector function and is a target for HIV infection

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Phenotypic Heterogeneity of Persistent Expansions of CD4+CD8+ T Cells

Cited by 37 publications

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Identification of an enriched CD4+ CD8α++ CD8β+ T-cell subset among tumor-infiltrating lymphocytes in human renal cell carcinoma

Identification of an enriched CD4+ CD8α++ CD8β+ T-cell subset among tumor-infiltrating lymphocytes in human renal cell carcinoma

Phenotypical heterogeneity of CD4+CD8+ double-positive chronic T lymphoid leukemia

CD4 on CD8+T cells directly enhances effector function and is a target for HIV infection

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CD4 on CD8⁺T cells directly enhances effector function and is a target for HIV infection