Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

Keir, Mary E.; Rosenberg, Michael; Sandberg, Johan K.; Jordan, Kimberly A.; Wiznia, Andrew; Nixon, Douglas F.; Stoddart, Cheryl A.; McCune, Joseph M.

doi:10.4049/jimmunol.169.5.2788

Cited by 40 publications

(37 citation statements)

References 50 publications

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“…HIV-1-induced IFN-␣ may up-regulate major histocompatibility complex (MHC) class I on thymic epithelial cells 30 and result in preferential selection of dysfunctional CD4 Ϫ CD8 ϩ thymocytes. 50 We show here that pDC-derived endogenous IFN-␣ directly impedes early T-cell lymphopoiesis. The presence of high levels of IFN-␣ may prevent T-cell regeneration in HIV-1 infection and contribute to the depletion of developing T cells by HIV-1.…”

Section: Discussionmentioning

confidence: 99%

Stimulated plasmacytoid dendritic cells impair human T-cell development

Schmidlin¹,

Dontje²,

Groot³

et al. 2006

Blood

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Thymic plasmacytoid dendritic cells (pDCs) are located predominantly in the medulla and at the corticomedullary junction, the entry site of bone marrowderived multipotential precursor cells into the thymus, allowing for interactions between thymic pDCs and precursor cells. We demonstrate that in vitro-generated pDCs stimulated with CpG or virus impaired the development of human autologous CD34 ؉ CD1a ؊ thymic progenitor cells into the T-cell lineage. Rescue by addition of neutralizing type I interferon (IFN) antibodies strongly implies that endogenously produced IFN-␣/␤ is responsible for this inhibitory effect. Consistent with this notion, we show that exogenously added IFN-␣ had a similar impact on IL-7-and Notch ligand-induced development of thymic CD34 ؉ CD1a ؊ progenitor cells into T cells, because induction of CD1a, CD4, CD8, and TCR/CD3 surface expression and rearrangements of TCR␤ V-DJ gene segments were severely impaired.In addition, IL-7-induced proliferation but not survival of the developing thymic progenitor cells was strongly inhibited by IFN-␣. It is evident from our data that IFN-␣ inhibits the IL-7R signal transduction pathway, although this could not be attributed to interference with either IL-7R proximal (STAT5, Akt/PKB, Erk1/2) or distal (p27 kip1 , pRb) events. IntroductionIn the thymus, T lymphocytes develop from bone marrowderived multipotential precursor cells. These early thymic precursors, which enter the thymus at the corticomedullary junction, 1 are also able to develop into natural killer (NK) cells, conventional dendritic cells (cDCs), and plasmacytoid DC (pDCs) 2 (reviewed by Spits 3 ). Human thymic precursors express CD34 and lack surface expression of CD1a, which is initiated upon commitment to the T-cell lineage. 4 Next to a small portion of TCR␥␦ ϩ T cells, mostly TCR␣␤ ϩ T cells develop, which sequentially rearrange T-cell receptor (TCR) ␤ genes followed by TCR␣ genes, up-regulate expression of CD4 and CD8, and undergo positive and negative selection before leaving the thymus as CD3 ϩ/hi /TCR-expressing, CD4 or CD8 singlepositive T cells (reviewed by Spits 3 and Spits et al 5 ).The thymic microenvironment consists of a network of various cell types, including epithelial cells and dendritic cells, which play essential roles in T-cell development. Thymic epithelial cells produce IL-7, the key cytokine for survival, proliferation, and development of T cells in the thymus, [6][7][8] and are involved in positive selection of T lymphocytes. Thymic CD11c ϩ cDCs, predominantly located in the medulla, 9,10 are involved in negative selection (reviewed by Wu and Shortman 11 ). CD11c Ϫ pDCs are present in the thymic medulla and at the corticomedullary junction, 9,10,12 but their contribution to T-cell development remains to be defined.While the function of thymic pDCs remains elusive, much insight has been obtained on the role of peripheral pDCs. Human pDCs, which are characterized by high surface expression of CD123 (IL-3R␣ chain) 13 and BDCA2 and BDCA4,14 are present in cord blood and...

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Section: Discussionmentioning

confidence: 99%

Stimulated plasmacytoid dendritic cells impair human T-cell development

Schmidlin¹,

Dontje²,

Groot³

et al. 2006

Blood

View full text Add to dashboard Cite

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“…This scenario is most likely because TCRs with high affinity for foreign pMHC show considerable self-reactivity and therefore are negatively selected in the thymus (37). Considering the HIV-infected thymus, a significant increase in the expression of MHC class I molecules was reported, with this MHC class I up-regulation resulting in decreased surface expression of CD8 Ags on thymocytes (38,39). This could lead to a decrease in the overall avidity of the TCR-CD8 signaling complex for self-pMHC ligands, allowing T cells with high affinity TCR to escape negative selection in the thymus and be exported to the periphery.…”

Section: Discussionmentioning

confidence: 99%

Functionally Impaired HIV-Specific CD8 T Cells Show High Affinity TCR-Ligand Interactions

Ueno

Tomiyama

Fujiwara

et al. 2004

The Journal of Immunology

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We eventually isolated two different clonotypic CD8 T cell subsets recognizing an HIV Pol-derived epitope peptide (IPLTEEAEL) in association with HLA-B35 from a chronic HIV-infected patient. By kinetic analysis experiments, the subsets showed a >3-fold difference in half-lives for the HLA tetramer in complex with the Pol peptide. In functional assays in vitro and ex vivo, both subsets showed substantial functional avidity toward peptide-loaded cells. However, the high affinity subset did not show cytolytic activity, cytokine production, or proliferation activity toward HIV-infected cells, whereas the moderate affinity one showed potent activities. Furthermore, using ectopic expression of each of the TCR genes into primary human CD8 T cells, the CD8 T cells transduced with the high affinity TCR showed greater binding activity toward the tetramer and impaired cytotoxic activity toward HIV-infected cells, corroborating the results obtained with parental CD8 T cells. Taken together, these data indicate that impaired responsiveness of T cells toward HIV-infected cells can occur at the level of TCR-ligand interactions, providing us further insight into the immune evasion mechanisms by HIV.

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“…tion, such as HIV infection, 41,42 and may represent long-lived anergic cells in some cases. 43 In LGL patients, we found an increased frequency of apoptotic T-cells compared with non-LGL patients and healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

et al. 2011

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The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8 þ T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27 À CD57 þ ) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8 high and CD8 low T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8 þ T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-c and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon.

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Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

Cited by 40 publications

References 50 publications

Stimulated plasmacytoid dendritic cells impair human T-cell development

Stimulated plasmacytoid dendritic cells impair human T-cell development

Functionally Impaired HIV-Specific CD8 T Cells Show High Affinity TCR-Ligand Interactions

Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

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