Tissue-resident memory T (TRM) cells serve as vanguards of anti-microbial host defense in nonlymphoid tissues, particularly at barrier epithelia and in organs with non-renewable cell types (e.g., brain). Here, we asked whether an augmented ability to sense antigen complemented their role as early alarms of pathogen invasion. Using mouse polyomavirus (MPyV), we show that brain-resident MPyV-specific CD8 T cells, unlike memory cells in the spleen, progressively increase binding to MHC class I tetramers and CD8 co-receptor expression. Using the two-dimensional micropipette adhesion frequency assay, we show that TRM cells in brain, as well as in kidney, express up to 20-fold higher affinity T cell receptors (TCRs) than splenic memory T cells, whereas effector cells express TCRs of similar high affinity in all organs. Together, these data demonstrate that TRM cells retain high TCR affinity, which endows them with the high antigen sensitivity needed for front-line defense against infectious agents.

Hand dermatitis is a common condition with a lifetime prevalence of 20%. Glove allergic contact dermatitis (ACD) is a very important dermatitis affecting health care workers, hairdressers, cleaning personnel, kitchen workers, craftsmen, construction workers, laboratory workers, and homemakers. Occupationally related cases may be severe and can result in significant disability. Glove ACD is most commonly due to exposure to rubber accelerators, which are compounds that are added to rubber during production to increase strength and durability. Given the known allergic potential of these compounds, glove manufacturing companies have reformulated gloves leading to the introduction of new rubber allergens. In this review, we will discuss risk factors for glove ACD, both common and uncommon allergens in gloves, common contact allergens that permeate gloves, and patch testing to help uncover the inciting allergen(s).

In this study, we investigate the basis of T cell recognition of myelin that governs the progression from acute symptoms into disease remission, relapse and chronic progression in a secondary progressive model of demyelinating disease. Until now, the frequency and affinity of myelin-reactive CD4 T cells that elicit relapsing-remitting disease have not been quantified. The micropipette adhesion frequency assay was used to obtain a sensitive and physiologically relevant two-dimensional measurement of frequency and TCR affinity for myelin, as the inherent low affinity does not allow the use of specific-peptide:MHC-II tetramers for this purpose. We found the highest affinity and frequency of polyclonal myelin oligodendrocyte glycoprotein (MOG)-reactive cells infiltrate the CNS during acute disease, while affinities during remission, relapse and chronic disease are not significantly different from each other. Frequency analysis revealed that the vast majority of CNS-infiltrating CD4 T cells are MOG-reactive at all time points demonstrating epitope spread is not a predominant factor for disease progression. Further, time points at which mice were symptomatic were characterized by an infiltration of Th17 cells in the CNS while symptom remission showed an enrichment of cells producing IFN-γ. Also, the ratio of regulatory T cells to Foxp3- CD4 T cells was significantly higher in the CNS at remission than during acute disease. The results of this study indicate that a high frequency of T cells specific for a single myelin antigen, rather than increased TCR affinity or epitope spread, govern the transition from acute symptoms through remission, relapse and chronic disease states.

Two pharmacologic approaches that are currently at the forefront of treating advanced cancer are those that center on disrupting critical growth/survival signaling pathways within tumor cells (commonly referred to as "targeted therapies") and those that center on enhancing the capacity of a patient's immune system to mount an antitumor response (immunotherapy). Maximizing responses to both of these approaches requires an understanding of the oncogenic events present in a given patient's tumor and the nature of the tumor-immune microenvironment. Although these 2 modalities were developed and initially used independently, combination regimens are now being tested in clinical trials, underscoring the need to understand how targeted therapies influence immunologic events. Translational studies and preclinical models have demonstrated that targeted therapies can influence immune cell trafficking, the production of and response to chemokines and cytokines, antigen presentation, and other processes relevant to antitumor immunity and immune homeostasis. Moreover, because these and other effects of targeted therapies occur in nonmalignant cells, targeted therapies are being evaluated for use in applications outside of oncology.

We studied the membrane transporters that mediate intracellular pH (pH(i)) recovery from acidification in brainstem neurons from chemosensitive regions of neonatal rats. Individual neurons within brainstem slices from the retrotrapezoid nucleus (RTN), the nucleus tractus solitarii (NTS), and the locus coeruleus (LC) were studied using a pH-sensitive fluorescent dye and fluorescence imaging microscopy. The rate of pH(i) recovery from an NH(4)Cl-induced acidification was measured, and the effects of inhibitors of various pH-regulating transporters determined. Hypercapnia (15% CO(2)) resulted in a maintained acidification in neurons from all three regions. Recovery in RTN neurons was nearly entirely eliminated by amiloride, an inhibitor of Na(+)/H(+) exchange (NHE). Recovery in RTN neurons was blocked approximately 50% by inhibitors of isoform 1 of NHE (NHE-1) but very little by an inhibitor of NHE-3 or by DIDS (an inhibitor of HCO(3)-dependent transport). In NTS neurons, amiloride blocked over 80% of the recovery, which was also blocked approximately 65% by inhibitors of NHE-1 and 26% blocked by an inhibitor of NHE-3. Recovery in LC neurons, in contrast, was unaffected by amiloride or blockers of NHE isoforms but was dependent on Na(+) and increased by external HCO(3)(-). On the basis of these findings, pH(i) recovery from acidification appears to be largely mediated by NHE-1 in RTN neurons, by NHE-1 and NHE-3 in NTS neurons, and by a Na- and HCO(3)-dependent transporter in LC neurons. Thus, pH(i) recovery is mediated by different pH-regulating transporters in neurons from different chemosensitive regions, but recovery is suppressed by hypercapnia in all of the neurons.