Project Details
Projekt
Molecular mechanisms of CD4 T-B cell communication and its disruption by HIV-1
Subject Area
Immunology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 538258788
B cell dysfunction is a hallmark of AIDS but the molecular mechanisms by which HIV undermines humoral immunity remain to be defined. We recently described that HIV-infected CD4 T cells are impaired in their helper function to B cells and that the HIV pathogenesis factor Nef is necessary and sufficient for this effect. Nef disrupts the communication of CD4 T cells to B cells, which results in an impairment of B cell activation and proliferation and thus of generation of high affinity antibodies. In preliminary work towards unraveling the mechanisms of Nef action, we identified a novel molecular surface in Nef that mediates this effect and identified several candidate host cell ligands that interact with this Nef surface in primary human CD4 T cells. The general mechanisms of CD4 T–B cell communication are also not well understood but involve information exchange across cellular membranes via cellular vesicles and protrusions. In addition, mechanosensing has been recognized as central element of immune cell activation but its roles in licensing CD4 T cells for helper function to B cells has not been studied. Since our preliminary results imply the involvement of mechanosensing in Nef-mediated interference, we hypothesize that Nef targets vesicular transport and/or plasma membrane and cytoskeleton remodeling to alter local mechanics of cell-cell interactions to disrupt T-B cell communication. We therefore aim at (i) defining the interaction partners by which HIV-1 Nef targets host cell ligands to disrupt T-B cell communication (specific aim (SA) 1) and (ii) characterizing the cell biology, micromechanic and biophysical principles of T-B cell communication to define the molecular mechanisms of Nef action (SA2). SA1 will provide insight into which host cell factors are hijacked by HIV-1 Nef to target specific steps of the humoral immune response. SA2 will assess which cellular structures mediate T-B cell communication, how mechanosensing and -transduction contributes to this process, and dissect the molecular mechanisms and ligands by which Nef affects organization and micromechanics of antigen-specific T-B cell interactions. Together, these synergistic and interdisciplinary studies will provide important new insights into the molecular patho-mechanisms of HIV and define general principles of immune cell communication.
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