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1.
Immunity ; 44(1): 167-178, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26795249

RESUMO

A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21(+)CD4(+) T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells. pTfh cells were functionally active and B cell helper quality differed depending on antigen specificity. Furthermore, we found higher frequency of pTfh cells in peripheral blood mononuclear cell specimens from the ALVAC+AIDSVAX (RV144) HIV vaccine trial associated with protective antibody responses compared to the non-protective DNA+Ad5 vaccine trial. Together, we identify IL-21(+)CD4(+) T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses.


Assuntos
Infecções por HIV/imunologia , Interleucinas/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Separação Celular , ELISPOT , Citometria de Fluxo , HIV-1/imunologia , Humanos , Reação em Cadeia da Polimerase em Tempo Real
2.
Nat Med ; 19(7): 930-3, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23793098

RESUMO

The contribution of HLA class II-restricted CD4(+) T cell responses to HIV immune control is poorly defined. Here, we delineated previously uncharacterized peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors. We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with HLA-DRB1*15:02 significantly associated with low viremia and HLA-DRB1*03:01 significantly associated with high viremia. Notably, a subgroup of HLA-DRB1 variants linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 variants linked with high viremia. Our data provide systematic evidence that HLA-DRB1 variant expression has a considerable impact on the control of HIV replication, an effect that seems to be mediated primarily by the protein specificity of CD4(+) T cell responses to HIV Gag and Nef.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Resistência à Doença/genética , Infecções por HIV/imunologia , HIV-1/imunologia , Alelos , Células Cultivadas , Estudos de Coortes , Resistência à Doença/imunologia , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/fisiologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Cadeias HLA-DRB1/metabolismo , Humanos , Carga Viral/genética , Carga Viral/fisiologia , Replicação Viral/genética , Replicação Viral/imunologia
3.
J Clin Invest ; 122(9): 3271-80, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22922259

RESUMO

HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. The depletion of antigen-specific CD4 T cells during HIV infection is therefore believed to impede the development of protective B cell immunity. Although several different HIV-related B cell dysfunctions have been described, the role of CD4 T follicular helper (TFH) cells in HIV infection remains unknown. Here, we assessed HIV-specific TFH responses in the lymph nodes of treatment-naive and antiretroviral-treated HIV-infected individuals. Strikingly, both the bulk TFH and HIV-specific TFH cell populations were significantly expanded in chronic HIV infection and were highly associated with viremia. In particular, GAG-specific TFH cells were detected at significantly higher levels in the lymph nodes compared with those of GP120-specific TFH cells and showed preferential secretion of the helper cytokine IL-21. In addition, TFH cell expansion was associated with an increase of germinal center B cells and plasma cells as well as IgG1 hypersecretion. Thus, our study suggests that high levels of HIV viremia drive the expansion of TFH cells, which in turn leads to perturbations of B cell differentiation, resulting in dysregulated antibody production.


Assuntos
Proliferação de Células , Infecções por HIV/imunologia , HIV-1/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Linfócitos B/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Doença Crônica , Proteínas de Ligação a DNA/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Imunoglobulina G/sangue , Interleucinas/metabolismo , Linfonodos/imunologia , Linfonodos/patologia , Proteínas Proto-Oncogênicas c-bcl-6 , Receptores CXCR5/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/fisiologia , Linfócitos T Auxiliares-Indutores/virologia , Viremia/virologia
4.
Cell Signal ; 22(12): 1882-90, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20688157

RESUMO

Asthma is characterised by antigen-mediated mast cell degranulation resulting in secretion of inflammatory mediators. Protein phosphatase 2A (PP2A) is a serine/threonine protein phosphatase composed of a catalytic (PP2A-C) subunit together with a core scaffold (PP2A-A) subunit and a variable, regulatory (PP2A-B) subunit. Previous studies utilising pharmacological inhibition of protein phosphatases have suggested a positive regulatory role for PP2A in mast cell degranulation. In support of this we find that a high okadaic acid concentration (1µM) inhibits mast cell degranulation. Strikingly, we now show that a low concentration of okadaic acid (0.1µM) has the opposite effect, resulting in enhanced degranulation. Selective downregulation of the PP2A-Cα subunit by short hairpin RNA also enhanced degranulation of RBL-2H3 mast cells, suggesting that the primary role of PP2A is to negatively regulate degranulation. PP2A-B subunits are responsible for substrate specificity, and carboxymethylation of the PP2A-C subunit alters B subunit binding. We show here that carboxymethylation of PP2A-C is dynamically altered during degranulation and inhibition of methylation decreases degranulation. Moreover downregulation of the PP2A-Bα subunit resulted in decreased MK2 phosphorylation and degranulation, whilst downregulation of the PP2A-B'δ subunit enhanced p38 MAPK phosphorylation and degranulation. Taken together these data show that PP2A is both a positive and negative regulator of mast cell degranulation, and this differential role is regulated by carboxymethylation and specific PP2A-B subunit binding.


Assuntos
Degranulação Celular/fisiologia , Mastócitos/fisiologia , Proteína Fosfatase 2/metabolismo , Subunidades Proteicas/metabolismo , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Metilação , Modelos Biológicos , Ácido Okadáico/farmacologia , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/fisiologia , Fosforilação , RNA Interferente Pequeno/metabolismo , Ratos , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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