Biology subjects

Pelicot-Biarnes, M.

Publications and source records attributed to Pelicot-Biarnes, M..

3 recordsLinked to original sources

bioRxiv2024

Decoupling individual host response and immune cell engager cytotoxic potency

Immune cell engagers are molecular agents, usually antibody-based constructs, engineered to recruit immune cells against cancer cells and kill them. They represent a versatile and powerful tool for cancer immunotherapy. Despite the multiplication of new engagers tested and accepted in the clinics, how molecular and cellular parameters influence their action is poorly understood. In particular, disentangling the respective role of host immune cells and engager biophysical characteristics is needed to improve their design and efficiency. Focusing here on harnessing antibody dependent Natural Killer cell cytotoxicity, we measure the efficiency of 6 original bispecific antibodies (bsAb), associating an anti-HER2 nanobody and an anti-CD16 nanobody. In vitro cytotoxicity data using primary human NK cells on different target cell lines exposing different antigen densities were collected, exhibiting a wide range of bsAb dose response. In order to rationalize our observations, we introduce a simple multiscale model, postulating that the density of bsAb bridging the two cells is the main parameter triggering the cytotoxic response. We introduce two new microscopic parameters: the surface cooperativity describing bsAb affinity at the bridging step and the threshold of bridge density determining the donor-dependent response. Both parameters permit to rank Abs and donors and to predict bsAb potency as a function of antibodies bulk affinities and receptor surface densities on cells. Our approach thus provides a general way to decouple donor response from immune engagers characteristics, rationalizing the landscape of molecule design.

biophysics↗

bioRxiv2023

Naive T lymphocytes chemotax to CCL21 but not to S1P-rich serum

Naive T lymphocytes traffic through the organism in their search for antigen, alternating between blood and secondary lymphoid organs. Lymphocyte homing to lymph nodes relies on the chemokine CCL21, while exit into efferent lymphatics relies on the sphingolipid S1P. Surprisingly, while both molecules are claimed chemotactic, a quantitative analysis of naive T lymphocyte migration along defined gradients is missing. Here, we used a reductionist in vitro approach to study the real-time, single-cell response of naive T lymphocytes to CCL21 and S1P-rich serum. Using high-throughput microfluidic and optical micropatterning ad hoc tools, we show that CCL21 triggers long-range chemotaxis whereas S1P-rich serum does not. Instead, S1P-rich serum triggers a transient polarization that may represent a brief transmigration step through exit portals. Our data thus validate naive T lymphocyte chemotaxis towards CCL21 but not S1P, which complements in vivo observations and is of interest for a better tailoring of immunosuppressive drugs.

biophysics↗

bioRxiv2022

Cellular forces during early spreading of T lymphocytes on ultra-soft substrates

Mechanical forces are increasingly recognized as critical regulators of T cell activation, yet their earliest dynamics remain poorly resolved. Here, we use traction force microscopy on ultra-soft, antigen-presenting-cell-like polyacrylamide substrates to quantify the first 15 minutes of force generation by Jurkat and primary human CD4 T cells under controlled activating conditions. By combining time-resolved stress mapping with spatial tensor analysis, we uncover previously unrecognized heterogeneity in early T cell mechanosensing. Rather than producing a single stereotyped mechanical response, T cells exhibit three distinct temporal force regimes: low-amplitude active fluctuations, intermittent force bursts, and sustained sigmoidal buildups of stress. These temporal programs tightly couple to spatial organization: fluctuating and intermittent behaviors associate with disordered stress distributions, whereas sustained sigmoidal responses predominantly accompany polarized, dipolar, and unexpectedly extensile stress patterns. Substrate stiffness strongly reshapes this distribution, with stiffer gels suppressing sustained high-energy responses and biasing cells toward fragmented mechanical engagement. Primary T cell subsets likewise display distinct force phenotypes: naive cells exhibit weak, fluctuating behaviors, whereas memory cells more readily enter sustained high-force states. Together, these findings support a two-stage model of early T cell mechanosensing in which filopodia-mediated probing generates low, intermittent forces that, upon sustained engagement, transition to a lamellipodia-driven spreading phase producing larger, persistent, and predominantly outward-directed stresses. This framework provides a mechanistic explanation for how substrate mechanics, receptor context, and immune cell state shape force generation during the earliest stages of activation. More broadly, our results identify force as a dynamic and structured component of antigen recognition rather than a passive consequence of T cell signaling. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/480084v4_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@29e24dorg.highwire.dtl.DTLVardef@1c8399forg.highwire.dtl.DTLVardef@3f29edorg.highwire.dtl.DTLVardef@d9a581_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗