Einfluss HIV-spezifischer CD4 T Zellantworten auf Antikörperfunktionen - Bedeutung für die HIV Impfstoffentwicklung
Virologie
Zusammenfassung der Projektergebnisse
Antibodies with a functional Fc region were previously associated with protection from HIV-1 acquisition and spontaneous suppression of viral replication. Unlike broadly neutralizing antibodies, they are not restricted to neutralizing epitopes and do not require unconventional structural traits to exert their antiviral activity. They, therefore, develop earlier after infection and can be detected in the majority of cases. The conditions under which these antibodies are generated, however, remain largely unknown. We demonstrated that the generation of HIV-1 Env-specific antibodies facilitating Fc-dependent innate immune responses, including neutrophil phagocytosis (ADNP), complement deposition (ADCD), and NK cell activation, likely depends on help provided by CD4+ T and peripheral T follicular helper (pTfh) cells secreting IL-21. Other proteins, including CD40L, IFNγ, and IL-4/13, involved in crosstalk between B and T cells were linked to the production of antibodies with functional Fc region but only when coexpressed with IL-21. As a potential source of these antibodies, we identified a subset of Envspecific memory B cells known to be expanded in chronic HIV-1 infection. The frequency and level of Blimp-1 expression in Env-specific tissue-like memory B cells (TLM) correlated with the functional CD4+ T cell subsets associated with robust antibody-dependent innate responses. Thus, our data suggest a mechanism responsible for the generation of antibodies with functional Fc region in chronically HIV-1 infected individuals that is based on CD4+ T cellinduced activation of memory B cells. Identification of helper T cells able to establish an efficient antibody response against HIV-1 might support the development of a vaccine or immunotherapy. We were able to show a possible dependence of the generation of HIV-1 Env specific antibodies that facilitate antibody-dependent innate immune responses to Env-specific IL-21-secreting CD4+ T and pTfh cells. Therefore, Env-specific pTfh cells expressing IL-21 might be a promising target for anti-HIV-1 vaccine design.
Projektbezogene Publikationen (Auswahl)
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Expansion of Stem Cell-Like CD4+ Memory T Cells during Acute HIV-1 Infection Is Linked to Rapid Disease Progression. J Virol. 2019 Jun 28;93(14):e00377-19
Pušnik J, Eller MA, Tassaneetrithep B, Schultz BT, Eller LA, Nitayaphan S, Kosgei J, Maganga L, Kibuuka H, Alter G, Michael NL, Robb ML, Streeck H
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Production of HIV-1 Env-Specific Antibodies Mediating Innate Immune Functions Depends on Cognate Interleukin-21- Secreting CD4+ T Cells. Journal of Virology Mar 2021, 95 (8) e02097-20
Jernej Pušnik, Stephanie Fischinger, Ulf Dittmer, Stefan Esser, Marit J. van Gils, Rogier W. Sanders, Galit Alter, Hendrik Streeck
