Reduced thymic maturation but normal effector function of CD8+ T cells in CD8 beta gene-targeted mice.

Fung-Leung, Wai-Ping; Kündig, Thomas M.; Ngo, Karen; Panakos, J; Sousa-Hitzler, Jean De; Wang, E.; Ohashi, Pamela S.; Mak, Tak W.; Lau, Catherine Y.

doi:10.1084/jem.180.3.959

Cited by 70 publications

(43 citation statements)

References 52 publications

(61 reference statements)

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“…However, the role of CD8␤ in mature T lymphocytes is unclear, since CD8␤ gene-targeted mice (lacking CD8␤) appear to have normal CD8 effector function (38). Recently, studies have demonstrated that CD8␤ is required for the recognition of peptide ligands (39), increases CD8 coreceptor function (40), and influences CD8␣-associated p56 lck kinase activity (41).…”

Section: Discussionmentioning

confidence: 99%

Activation of Macrophage CD8: Pharmacological Studies of TNF and IL-1β Production

Lin

Hirji

Stenton

et al. 2000

The Journal of Immunology

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Previously, we demonstrated that rat macrophages express CD8 and that Ab to CD8 stimulates NO production. We confirm that CD8 is expressed by rat macrophages and extend understanding of its functional significance. Activation of CD8α (OX8 Ab) on alveolar macrophages stimulated mRNA expression for TNF and IL-1β and promoted TNF and IL-1β secretion. Similarly, OX8 Ab (CD8α) stimulated NR8383 cells to secrete TNF, IL-1β, and NO. Activation of CD8β (Ab 341) on alveolar macrophages increased mRNA expression for TNF and IL-1β and stimulated secretion of TNF, but not IL-1β. Interestingly, anti-CD8 Abs did not stimulate IFN-γ or PGE2 production, or phagocytosis by macrophages. OX8 (CD8α)-induced TNF and IL-1β production by macrophages was blocked by inhibitors of protein tyrosine kinase(s), PP1, and genistein, but not by phosphatidylinositol-3 kinase inhibitor, wortmannin. Moreover, OX8 stimulated protein tyrosine kinase activity in NR8383 cells. Further analysis of kinase dependence using antisense to Syk kinase demonstrated that TNF, but not IL-1β, stimulation by CD8α is Syk dependent. By contrast, protein kinase C inhibitor Ro 31-8220 had no effect on OX8-induced TNF production, whereas OX8-induced IL-1β production was blocked by Ro 31-8220. Thus, there are distinct signaling mechanisms involved in CD8α (OX8)-induced TNF and IL-1β production. In summary, macrophages express CD8 molecules that, when activated, stimulate TNF and IL-1β expression, probably through mechanisms that include activation of Src and Syk kinases and protein kinase C. These findings identify a previously unknown pathway of macrophage activation likely to be involved in host defense and inflammation.

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Section: Discussionmentioning

confidence: 99%

Activation of Macrophage CD8: Pharmacological Studies of TNF and IL-1β Production

Lin

Hirji

Stenton

et al. 2000

The Journal of Immunology

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“…8 V␣24 + T cells represent a human homologue of V␣14 + T cells which differentiate extrathymically in mice. 9,10 CD8␣/␣ + T cells may also differentiate extrathymically in humans because CD8␣/␣ + T cells reside in intestinal mucosa in nude mice, [11][12][13] and a large number of CD8␣/␣ + T cells was identified in the human fetal intestine. 14 As little is known about the relative contribution of the three pathways to T cell regeneration after allogeneic BMT, we analyzed T cell regeneration using putative phenotypic markers of thymus-dependent pathway (CD4 + CD45RA + T cells) and thymus-independent pathways (V␥9 + V␦2 + T cells, V␣24 + T cells, CD8␣/␣ + T cells and CD28 − T cells) after allogeneic BMT in children.…”

Section: Discussionmentioning

confidence: 99%

Thymus-independent expansion of T lymphocytes in children after allogeneic bone marrow transplantation

Honda

Takada

Nagatoshi

et al. 2000

Bone Marrow Transplant

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Summary:The contribution of the thymus-dependent pathway and thymus-independent pathways for T cell regeneration after BMT in children is still unclear. We analyzed the kinetics of T cell regenerative pathways after allogeneic BMT. The number of CD4 + CD45RA + T cells, a thymusdependent population, was very low until 3 months after BMT. The numbers of CD28 − T cells and CD8 + T cells expressing CD8␣/␣ homodimer (CD8␣/␣ + T cells), a thymus-independent population, increased shortly after BMT, beyond the levels of healthy children in some patients. The numbers of V␥9 + V␦2 + and V␣24 + T cells, which represent populations of extrathymic development, were less than 200/ l during the 6 months after BMT. There was a significant inverse correlation between the percentages of CD4 + CD45RA + and CD28 -T cells at 1 month, and a positive correlation between the percentages of CD28 − and CD8␣/␣ + T cells at 2 and 3 months after BMT. The mean age at BMT was higher in patients with a high level of CD8␣/␣ + T cells than in those without an increase in these cells, suggesting the influence of thymic function on the regenerative pathways. These results suggest that the thymus-independent pathway is the dominant source of T cells even in children shortly after allogeneic BMT. Bone Marrow Transplantation (2000) 25, 647-652. Keywords: T cell regeneration; allogeneic BMT; thymus-independent; CD8␣/␣ + T cells T cell populations recover via thymus-dependent and thymus-independent pathways after T cell depletion following chemotherapy or BMT. CD4 + CD45RA + T cells are suggested to be thymus-dependent because (1) CD4 + T cells express the CD45RA antigen when they are exported from the thymus; 1-2 (2) thymectectomized hosts fail to reconstitute CD4 + CD45RA + T cells for a long period after BMT compared with thymus-bearing hosts; 3 (3) reconstitution of CD4 + CD45RA + T cells coincides with the enlargement of thymus size after high-dose chemotherapy; 4 and (4) an inverse relationship between patients' ages and the reconsti- tution of CD4 + CD45RA + T cells is observed after intensive chemotherapy. 4 Thymus-independent T cell regeneration after BMT includes extrathymic differentiation, and peripheral expansion of mature T cells derived from donor bone marrow cells. 5-6 CD8 + CD28 − T cells appear to regenerate thymusindependently, since CD8 + CD28 − T cells reconstitute rapidly after BMT in spite of the therapy-related thymic atrophy. 7 V␥9 + V␦2 + T cells, constituting a minor population in the peripheral blood of healthy individuals, differentiate extrathymically. 8 V␣24 + T cells represent a human homologue of V␣14 + T cells which differentiate extrathymically in mice. 9,10 CD8␣/␣ + T cells may also differentiate extrathymically in humans because CD8␣/␣ + T cells reside in intestinal mucosa in nude mice, [11][12][13] and a large number of CD8␣/␣ + T cells was identified in the human fetal intestine. 14 As little is known about the relative contribution of the three pathways to T cell regeneration after allogeneic BMT, we analyzed T c...

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“…To determine whether DAF regulates CD8 ϩ T cell immunity, we infected groups of WT and Daf-1 Ϫ/Ϫ mice with LCMV-Armstrong, a virus strain that causes acute infection and a strong CD8 ϩ T cell response in the mouse (15,18,19). On day 6, 7, or 8 postinfection, mice were sacrificed, and the percentage and total number of CD4 ϩ and CD8 ϩ T cells in their spleens were determined by FACS.…”

Section: Daf-1 ϫ/ϫ Mice Had Markedly Increased Total and Ag-specific mentioning

confidence: 99%

Complement-Dependent Enhancement of CD8+ T Cell Immunity to Lymphocytic Choriomeningitis Virus Infection in Decay-Accelerating Factor-Deficient Mice

Fang

Miwa

Shen

et al. 2007

The Journal of Immunology

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Decay-accelerating factor (DAF, CD55) is a GPI-anchored membrane protein that regulates complement activation on autologous cells. In addition to protecting host tissues from complement attack, DAF has been shown to inhibit CD4+ T cell immunity in the setting of model Ag immunization. However, whether DAF regulates natural T cell immune response during pathogenic infection is not known. We describe in this study a striking regulatory effect of DAF on the CD8+ T cell response to lymphocytic choriomeningitis virus (LCMV) infection. Compared with wild-type mice, DAF knockout (Daf-1−/−) mice had markedly increased expansion in the spleen of total and viral Ag-specific CD8+ T cells after acute or chronic LCMV infection. Splenocytes from LCMV-infected Daf-1−/− mice also displayed significantly higher killing activity than cells from wild-type mice toward viral Ag-loaded target cells, and Daf-1−/− mice cleared LCMV more efficiently. Importantly, deletion of the complement protein C3 or the receptor for the anaphylatoxin C5a (C5aR) from Daf-1−/− mice reversed the enhanced CD8+ T cell immunity phenotype. These results demonstrate that DAF is an important regulator of CD8+ T cell immunity in viral infection and that it fulfills this role by acting as a complement inhibitor to prevent virus-triggered complement activation and C5aR signaling. This mode of action of DAF contrasts with that of CD59 in viral infection and suggests that GPI-anchored membrane complement inhibitors can regulate T cell immunity to viral infection via either a complement-dependent or -independent mechanism.

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Reduced thymic maturation but normal effector function of CD8+ T cells in CD8 beta gene-targeted mice.

Cited by 70 publications

References 52 publications

Activation of Macrophage CD8: Pharmacological Studies of TNF and IL-1β Production

Activation of Macrophage CD8: Pharmacological Studies of TNF and IL-1β Production

Thymus-independent expansion of T lymphocytes in children after allogeneic bone marrow transplantation

Complement-Dependent Enhancement of CD8+ T Cell Immunity to Lymphocytic Choriomeningitis Virus Infection in Decay-Accelerating Factor-Deficient Mice

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