Weakened germinal center responses by the aged immune system result in diminished immunity against pathogens and reduced efficacy of vaccines. Prolonged contacts between activated B cells and CD4+ T ...cells are crucial to germinal center formation and T follicular helper cell (Tfh) differentiation, but it is unclear how aging impacts the quality of this interaction. Peptide immunization confirmed that aged mice have decreased expansion of antigen‐specific germinal center B cells and reduced antibody titers. Furthermore, aging was associated with accumulated Tfh cells, even in naïve mice. Despite increased numbers, aged Tfh had reduced expression of master transcription factor BCL6 and increased expression of the ectonucleotidase CD39. In vitro activation revealed that proliferative capacity was maintained in aged CD4+ T cells, but not the costimulatory molecule CD40L. When activated in vitro by aged antigen‐presenting cells, young CD4+ naïve T cells generated reduced numbers of activated cells with upregulated CD40L. To determine the contribution of cell‐extrinsic influences on antigen‐specific Tfh induction, young, antigen‐specific B and CD4+ T cells were adoptively transferred into aged hosts prior to peptide immunization. Transferred cells had reduced expansion and differentiation into germinal center B cell and Tfh and reduced antigen‐specific antibody titers when compared to young hosts. Young CD4+ T cells transferred aged hosts differentiated into Tfh cells with reduced PD‐1 and BCL6 expression, and increased CD39 expression, though they maintained their mitochondrial capacity. These results highlight the role of the lymphoid microenvironment in modulating CD4+ T cell differentiation, which contributes to impaired establishment and maintenance of germinal centers.
Aging is associated with poor induction of germinal centers, organized lymphoid tissue structures that are important for infection and vaccination responses. CD4+ T cells provide help to B cells during germinal center induction, but the mechanisms by which they fail to support germinal centers are still unclear. Here we uncouple T cell‐intrinsic versus extrinsic changes with age that contribute to impaired CD4+ T‐cell activation and differentiation.
Background
Antibody-based therapies blocking the programmed cell death-1/ligand-1 (PD-1/PD-L1) axis have provided unprecedent clinical success in cancer treatment. Acquired resistance, however, ...frequently occurs, commonly associated with the upregulation of additional inhibitory molecules. Diacylglycerol kinase (DGK)
α
limits the extent of Ras activation in response to antigen recognition, and its upregulation facilitates hypofunctional, exhausted T cell states. Pharmacological DGK
α
targeting restores cytotoxic function of chimeric antigen receptor and CD8
+
T cells isolated from solid tumors, suggesting a mechanism to reverse T cell exhausted phenotypes. Nevertheless, the contribution of DGK
α
downstream of the PD-1/PD-L1 inhibitory axis in human T cells and the consequences of combining DGK
α
and anti-PD-1/PD-L1 inhibitors are still unresolved relevant issues.
Materials and methods
We used a human triple parameter reporter cell line to investigate DGK
α
contribution to the PD-1/PD-L1 inhibitory pathway. We also addressed the impact of deleting DGK
α
expression in the growth dynamics and systemic tumor-derived effects of a PD-1-related tumor model, the MC38 colon adenocarcinoma.
Results
We identify DGK
α
as a contributor to the PD-1/PD-L1 axis that strongly limits the Ras/ERK/AP-1 pathway. DGK
α
function reinforces exhausted T cell phenotypes ultimately promoting tumor growth and generalized immunosuppression. Pharmacological DGKα inhibition selectively enhances AP-1 transcription and, importantly, cooperates with antibodies blocking the PD-1/PD-L1 interrelation.
Conclusions
Our results indicate that DGK
α
inhibition could provide an important mechanism to revert exhausted T lymphocyte phenotypes and thus favor proper anti-tumor T cell responses. The cooperative effect observed after PD-1/PD-L1 and DGK
α
blockade offers a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer.
Dendritic cells (DCs) are a heterogeneous group of antigen-presenting innate immune cells that regulate adaptive immunity, including against cancer. Therefore, understanding the precise activities of ...DCs in tumours and patients with cancer is important. The classification of DC subsets has historically been based on ontogeny; however, single-cell analyses are now additionally revealing a diversity of functional states of DCs in cancer. DCs can promote the activation of potent antitumour T cells and immune responses via numerous mechanisms, although they can also be hijacked by tumour-mediated factors to contribute to immune tolerance and cancer progression. Consequently, DC activities are often key determinants of the efficacy of immunotherapies, including immune-checkpoint inhibitors. Potentiating the antitumour functions of DCs or using them as tools to orchestrate short-term and long-term anticancer immunity has immense but as-yet underexploited therapeutic potential. In this Review, we outline the nature and emerging complexity of DC states as well as their functions in regulating adaptive immunity across different cancer types. We also describe how DCs are required for the success of current immunotherapies and explore the inherent potential of targeting DCs for cancer therapy. We focus on novel insights on DCs derived from patients with different cancers, single-cell studies of DCs and their relevance to therapeutic strategies.
Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS‐CoV‐2. However, dual strategies combining virus neutralization and immune ...response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross‐priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT, are first generated by grafting an anti‐RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo‐EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high‐avidity neutralizing interaction. Then, by C‐terminal fusion of an anti‐DNGR‐1 scFv to TNT, the bispecific trimerbody TNTDNGR‐1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross‐priming. Therapeutic administration of TNTDNGR‐1, but not TNT, protects K18‐hACE2 mice from a lethal SARS‐CoV‐2 infection, boosting virus‐specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus‐neutralizing antibody activity and demonstrate the therapeutic potential of the Fc‐free strategy that can be used advantageously to provide both immediate and long‐term protection against SARS‐CoV‐2 and other viral infections.
Here they generate a bispecific Fc‐free trimeric antibody to neutralize and target SARS‐CoV‐2 virions to type 1 conventional dendritic cells and promote T cell cross‐priming. Therapeutic administration protected mice from a lethal infection, boosting virus‐specific humoral and CD8+ T cell immune responses. The results highlight the potential of bispecific trimerbodies with neutralizing and vaccine‐like action to provide both immediate and long‐term protection against SARS‐CoV‐2 and other viral infections.
