Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity.

Cytotoxic lymphocytes fight pathogens and cancer by forming immune synapses with infected or transformed target cells and then secreting cytotoxic perforin and granzyme into the synaptic space, with potent and specific killing achieved by this focused delivery. The mechanisms that establish the precise location of secretory events, however, remain poorly understood. Here we use single cell biophysical measurements, micropatterning, and functional assays to demonstrate that localized mechanotransduction helps define the position of secretory events within the synapse. Ligand-bound integrins, predominantly the αLß2 isoform LFA-1, function as spatial cues to attract lytic granules containing perforin and granzyme and induce their fusion with the plasma membrane for content release. LFA-1 is subjected to pulling forces within secretory domains, and disruption of these forces via depletion of the adaptor molecule talin abrogates cytotoxicity. We thus conclude that lymphocytes employ an integrin-dependent mechanical checkpoint to enhance their cytotoxic power and fidelity.

Multi-Factor Clustering Incorporating Cell Motility Predicts T Cell Expansion Potential.

Expansion of an initial population of T cells is essential for cellular immunotherapy. In Chronic Lymphocytic Leukemia (CLL), expansion is often complicated by lack of T cell proliferation, as these cells frequently show signs of exhaustion. This report seeks to identify specific biomarkers or measures of cell function that capture the proliferative potential of a starting population of cells. Mixed CD4+/CD8+ T cells from healthy donors and individuals previously treated for CLL were characterized on the basis of proliferative potential and in vitro cellular functions. Single-factor analysis found little correlation between the number of populations doublings reached during expansion and either Rai stage (a clinical measure of CLL spread) or PD-1 expression. However, inclusion of in vitro IL-2 secretion and the propensity of cells to align onto micropatterned features of activating proteins as factors identified three distinct groups of donors. Notably, these group assignments provided an elegant separation of donors with regards to proliferative potential. Furthermore, these groups exhibited different motility characteristics, suggesting a mechanism that underlies changes in proliferative potential. This study describes a new set of functional readouts that augment surface marker panels to better predict expansion outcomes and clinical prognosis.

Ocular Autoimmune Systemic Inflammatory Infectious Study - Report 3: Posterior and Panuveitis.

PURPOSE: To report the pattern of posterior and panuveitis at a tertiary referral center in Singapore. METHODS: Subgroup retrospective analysis of 334 new posterior and panuveitis cases, from the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) database. Descriptive analysis was performed and visual outcome and complications were reported. RESULTS: The etiology for posterior uveitis and panuveitis was infectious in 162 patients (48.5%), non-infectious in 144 patients (43.1%), and idiopathic in 28 patients (8.4%). More patients with bilateral disease had a non-infectious etiology (n = 82, 50.9%) (p = 0.012). The most common complication was epiretinal membrane (n = 20, 12.3%) for the infectious group and cystoid macular edema (n = 12, 8.3%) for the non-infectious group. CONCLUSIONS: The proportion of etiologies in our cohort varies from other studies. Understanding the variations and demographic associations allows the diagnosis and management of posterior and panuveitis to be further improved.

Viral posterior uveitis.

The causes of posterior uveitis can be divided into infectious, autoimmune, or masquerade syndromes. Viral infections, a significant cause of sight-threatening ocular diseases in the posterior segment, include human herpesviruses, measles, rubella, and arboviruses such as dengue, West Nile, and chikungunya virus. Viral posterior uveitis may occur as an isolated ocular disease in congenital or acquired infections or as part of a systemic viral illness. Many viruses remain latent in the infected host with a risk of reactivation that depends on various factors, including virulence and host immunity, age, and comorbidities. Although some viral illnesses are self-limiting and have a good visual prognosis, others, such as cytomegalovirus retinitis or acute retinal necrosis, may result in serious complications and profound vision loss. Since some of these infections may respond well to antiviral therapy, it is important to work up all cases of posterior uveitis to rule out an infectious etiology. We review the clinical features, diagnostic tools, treatment regimens, and long-term outcomes for each of these viral posterior uveitides.