Biology subjects

Capera, J.

Publications and source records attributed to Capera, J..

4 recordsLinked to original sources

bioRxiv2025

STAT3 phosphorylation in the rheumatoid arthritis immunological synapse

Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4+ T cells. Our data demonstrates that Lck mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic Lck/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.

immunology↗

bioRxiv2024

A resource for extracellular vesicles from activated CD4 T cells that relay pro-inflammatory signals

CD4 T helper cells (TH cells) play a vital role in coordinating and amplifying the immune response to specific pathogens. They constitutively produce different kinds of extracellular vesicles (EVs), which mediate cell-to cell communication and play diverse roles in immune regulation and inflammatory processes. Here we provide a resource documenting the composition of activated TH cell EVs and demonstrating their ability to instigate pro-inflammatory response in antigen-presenting cells (APCs). EVs were characterized by lipidomics, proteomics, and NanoFCM. The activated TH cells derived EVs (act-EVs) were found to be enriched in TH cell-specific proteins, transmembrane and cytosolic EV marker proteins, and HLA proteins relative to resting CD4 T cells EVs (rest-EVs). The pro-inflammatory effect of act-EVs vs rest-EVs on donor matched APCs were characterized by chemokine and cytokine profiling and flow cytometry analysis. There was no discernible contrast in endotoxin levels between act-EVs and rest-EVs. Functional distinctions were seen to arise from variations in the content and composition of these EVs. Moreover, we validated our findings with an in-vivo investigation in mice, demonstrating the recruitment of monocytes, dendritic cells (DCs), neutrophils, and NK cells in the spleen, accompanied by the release of pro-inflammatory cytokines in the serum after administering act-EVs. In summary, this study sheds light on the role of TH cell released EVs in modulating the immune response during pro-inflammatory responses and this resource provides a foundation for development of novel therapeutics on EV based scaffolds.

immunology↗

bioRxiv2024

Synaptic synergy of T cell receptor and interleukin 2 receptor in CD8+ T cells

Interleukin 2 (IL2) promotes T cell proliferation and differentiation, making it a central target in immunotherapies. T cells fine-tune their sensitivity to and consumption of IL2 by regulating surface expression and composition of the IL2 receptor. Following antigen recognition, IL2 receptor signaling is shared through polarized interactions in T cell aggregates. However, how IL2 function is integrated during earlier antigen-dependent T cell synapses is unknown. Here, we demonstrate a synergistic effect between the T cell receptor (TCR) and IL2 receptor signaling at the immunological synapse of CD8+ T cells with supported lipid bilayers. TCR and IL2 signaling overlapped in space and time, potentiating each other when simultaneously triggered. Immuno-STATs, a safe and effective new class of immunotherapeutics, which fuse IL2 and peptide-major histocompatibility complex (pMHC) in a single molecule to expand antigen-specific CD8+ T cells, enhanced both TCR and IL2 signaling and promoted antigen specific T-T immunological synapses.

immunology↗

bioRxiv2021

Mapping of the autophagosomal degradome identifies IL-7Rα as key cargo in proliferating CD4+ T-cells

CD4+ T cells orchestrate both humoral and cytotoxic immune responses. While it is known that CD4+ T cell proliferation relies on autophagy, direct identification of the autophagosomal cargo involved is still missing. Here, we created a transgenic mouse model, which, for the first time, enables us to directly map the proteinaceous content of autophagosomes in any primary cell by LC3 proximity labelling. IL-7R, a cytokine receptor mostly found in naive and memory T cells, was reproducibly detected in autophagosomes of activated CD4+ T cells. Consistently, CD4+ T cells lacking autophagy showed increased IL-7R surface expression, while no defect in internalisation was observed. Mechanistically, excessive surface IL-7R sequestrates the common gamma chain, impairing the IL-2R assembly and downstream signalling crucial for T cell proliferation. This study provides proof-of-principle that key autophagy substrates can be reliably identified with this model to help mechanistically unravel autophagys contribution to healthy physiology and disease.

immunology↗