Immunological Fingerprints of Controllers Developing Neutralizing HIV-1 Antibodies

Abstract

The induction of broadly neutralizing antibodies (bnAbs) is highly desired for an effective vaccine against HIV-1. Typically, bnAbs develop in patients with high viremia, but they can also evolve in some untreated HIV-1 controllers with low viral loads. Here, we identify a subgroup of neutralizer-controllers characterized by myeloid DCs (mDCs) with a distinct inflammatory signature and a superior ability to prime T follicular helper (Tfh)-like cells in an STAT4-dependent fashion. This distinct immune profile is associated with a higher frequency of Tfhlike cells in peripheral blood (pTfh) and an enrichment for Tfh-defining genes in circulating CD4 + T cells. Correspondingly, monocytes from this neutralizer controller subgroup upregulate genes encoding for chemotaxis and inflammation, and they secrete high levels of IL-12 in response to TLR stimulation. Our results suggest the existence of multi-compartment immune networks between mDCs, Tfh, and monocytes that may facilitate the development of bnAbs in a subgroup of HIV-1 controllers.

COVID-19 severity associates with pulmonary redistribution of CD1c+ DCs and inflammatory transitional and nonclassical monocytes

“…specific functional assays. In addition, CD1c + cDCs are known to support CD4 + T cell responses and stimulate follicular helper T cells required for effective humoral antiviral adaptive immunity (14). While it has been proposed that protection against SARS-CoV-2 might also be at least partially mediated by specific Abs (41), the role of CD1c + DCs inducing Tfh responses in these patients has not been addressed in our study and requires further research.…”

“…Dendritic cells (DCs) are a heterogeneous lineage of antigen-presenting cells (APCs) that include different subsets of CD123 hi plasmacytoid DCs (pDCs) and conventional DCs (cDCs, CD1c + and CD141 + ). These innate cells are critical for activation of adaptive CD4 + and CD8 + T cell responses and are key players in the immune responses to viral and bacterial infections (13)(14)(15)(16)(17). A second important player in the immune response against pathogens are Mo, which can be subdivided into immature classical (CD14 ++ CD16 -, C) and more differentiated inflammatory transitional (CD14 + CD16 + , T) and nonclassical (CD14 -CD16 ++ , NC) subsets.…”

Differential Redistribution of Activated Monocyte and Dendritic Cell Subsets to the Lung Associates with Severity of COVID-19

“…These data might support a defect on the priming, the maintenance or exhaustion of virus-specific CD8 + T cells in the lungs; however these issues must be investigated in depth. In addition, CD1c + cDCs are known to support CD4 + T cell responses and stimulate follicular helper T cells required for effective humoral antiviral adaptive immunity (13). While it has been proposed that protection against SARS-CoV-2 might also be at least partially mediated by specific antibodies (32), the role of CD1c + DCs inducing Tfh responses in these patients has not been addressed in our study and requires further research.…”

“…Dendritic cells (DC) are a heterogeneous lineage of antigen presenting cells (APC), which includes different subsets of CD123 hi plasmacytoid DCs (pDC) and conventional (cDC) CD1c + and CD141 + DCs. These innate cells are critical for activation of adaptive CD4 + and CD8 + T cell responses, and are key players in the immune responses to viral and bacterial infections (12)(13)(14)(15)(16). A second important player in the immune response against pathogens are monocytes (Mo), which can be subdivided in immature classical (CD14 ++ CD16 -, C) and more differentiated inflammatory transitional (CD14 + CD16 + , T) and non-classical (CD14 -CD16 ++ , NC) subsets.…”

Tailored Dc Induce Protective Hiv-1 Specific Polyfunctional Cd8+ T Cells in the Lymphoid Tissue From Humanized BLT Mice

“…While previous efforts to achieve this goal have failed (1, 2), the scientific community has come to understand that the induction of effective and durable HIV-1-specific T cell responses in different anatomical compartments will most likely require the targeting and fine-tuning of specific innate immune cell subsets, such as dendritic cells (DC). DC play a critical role during the priming of specific adaptive immune responses, since they are capable of both efficiently presenting antigens (Ags) to T cells and also mediating the polarization of effector lymphocytes (3)(4)(5)(6)(7). In fact, DCbased therapeutic vaccines have shown very promising results in clinical trials for cancer therapy (8).…”