The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.

Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG <sub>4</sub> ) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG <sub>4</sub> -HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners

Cellular Therapy with Engineered T Cells, Efficacy and Side Effects

The cellular basis of cancer immune surveillance, already hypothesized in ancient times, was only demonstrated with the advent of HSCT. Indeed, the discovery of the nature of GVHD and its antileukemic effects (Weiden et al

Normal and altered masticatory load impact on the range of craniofacial shape variation: An analysis of pre-Hispanic and modern populations of the American Southern Cone

The reduction of masticatory load intensity resulting from dietary changes in human evolution has been proposed as an important factor that alters craniofacial shape in past and current populations. However, its impact on craniofacial variation and on the perceived differences among populations is unclear. The maxillomandibular relationship, which alters masticatory force direction, is a factor often neglected but it can contribute to variation in craniofacial morphology, particularly among modern/urban populations where the prevalence of dental malocclusions is greater than in prehistoric populations. This study investigates the influence of masticatory load intensity and maxillomandibular relationship as a proxy for force direction on the human craniofacial skeleton. By using 3D imaging and geometric morphometrics, we analyzed craniofacial shape variation among 186 individuals from pre-Hispanic and modern Chilean and Argentinean populations that differ in diet consistency (a proxy for masticatory load intensity) and maxillomandibular relationship. We predicted that masticatory load would have a subtle effect on the upper craniofacial bones and that this would be more marked in the maxilla. Our results showed no clear influence of masticatory load on craniofacial shape, particularly in modern/urban populations. Allometry, on the contrary, shows a stronger effect. The degree of integration between the upper craniofacial bones and the load-bearing maxilla depends on masticatory load intensity, decreasing from high to low but showing a conservative pattern of covariation among the groups. The degree of variation in the shape of the maxilla is greater than the upper craniofacial bones. These results suggest that masticatory load has a limited effect in determining differences in craniofacial morphology among populations. This effect is slightly greater for the maxillary region of the face. We propose that the reduction of functional constraints is key to greater shape variation found in modern/urban populations