Terri H. Finkel

At the interface between T cell and antigen-presenting cell (APC), peptide antigen presented by MHC (pMHC) binds to the T cell receptor (TCR) and initiates signaling. The mechanism of TCR signal initiation, or triggering, remains unclear. An interesting aspect of this puzzle is that although soluble agonist pMHCs cannot trigger TCR even at high concentrations, the same ligands trigger TCR very efficiently on the surface of APCs. Here, using lipid bilayers or plastic-based artificial APCs with defined components, we identify the critical APC-associated factors that confer agonist pMHCs with such potency. We found that CD4⁺ T cells are triggered by very low numbers of monomeric agonist pMHCs anchored on fluid lipid bilayers or fixed plastic surfaces, in the absence of any other APC surface molecules. Importantly, on bilayers, plastic surfaces, or real APCs, endogenous pMHCs did not enhance TCR triggering. TCR triggering, however, critically depended upon the adhesiveness of the surface and an intact T cell actin cytoskeleton. Based on these observations, we propose the receptor deformation model of TCR triggering to explain the remarkable sensitivity and specificity of TCR triggering. Using the T cell receptor (TCR) as a sensor, T cells of the immune system constantly migrate in lymphoid organs and probe the surface of antigen-presenting cells (APCs) for foreign antigens, a sign of pathogen infection. Antigen binding by TCRs leads to T cell activation and subsequent immune response to combat the pathogens. Interestingly, although T cells respond well to antigens on APCs, they do not recognize the same antigens in solution. What is it that makes antigens on APCs recognizable? To address this, we used lipid bilayers and plastic surfaces to construct artificial APCs with defined antigen number, composition, and configuration. We found that T cells respond to very few individual foreign antigens on artificial APCs, and contrary to some current opinion, formation of antigen clusters on APCs is not required for antigen recognition by T cells. TCR triggering, however, requires T cell adhesion to the APC surface and then occurs only if the T cells are able to move. We propose that at the dynamic T cell–APC interface, antigen on APCs activates T cells by applying force to the TCR and deforming its structure, which cannot be achieved by soluble antigens due to their lack of anchorage.

Background: Central nervous system involvement occurs in as many as twenty percent of Takayasu arteritis cases. When central nervous system disease is present, it typically manifests as cerebral ischemia or stroke. There are rare reports of intracranial aneurysms in adults with Takayasu arteritis, but none in children. Case presentation: We describe a case of Takayasu arteritis in an 18 month old girl who presented with a ruptured cerebral aneurysm. Full body magnetic resonance angiography revealed bilateral iliac, pelvic and intragluteal aneurysms, irregular terminal aorta, and stenotic renal arteries. Iliac vessel biopsy showed a lymphocytic infiltrate and giant cells localized to the internal elastica. Conclusion: This case highlights cerebral aneurysm as a highly unusual initial manifestation of Takayasu arteritis and demonstrates the challenges of diagnosis, treatment, and assessment of response to therapy in TA in children.

Through T cell receptors (TCRs), T cells can detect and respond to very small numbers of foreign peptides among a huge number of self‐peptides presented by major histocompatibility complexes (pMHCs) on the surface of antigen‐presenting cells (APCs). How T cells achieve such remarkable sensitivity and specificity through pMHC‐TCR binding is an intensively pursued issue in immunology today;the key question is how pMHC‐TCR binding initiates, or triggers, a signal from TCRs. Multiple competing models have been proposed, none of which fully explains the sensitivity and specificity of TCR triggering. What has been omitted from existing theories is that the pMHC‐TCR interaction at the T cell/APC interface must be under constant mechanical stress, due to the dynamic nature of cell‐cell interaction. Taking this condition into consideration, we propose the receptor deformation model of TCR triggering. In this model, TCR signaling is initiated by conformational changes of the TCR/CD3 complex, induced by a pulling force originating from the cytoskeleton and transmitted through pMHC‐TCR binding interactions with enough strength to resist rupture. By introducing mechanical force into a model of T cell signal initiation, the receptor deformation model provides potential mechanistic solutions to the sensitivity and specificity of TCR triggering. Ma, Z., Janmey, P. A., Finkel, T. H. The receptor deformation model of TCR triggering. FASEB J. 22, 1002–1008 (2008)

The chemokine receptor, CXCR4, serves as the primary coreceptor for entry of T-cell tropic human immunodeficiency virus (HIV). Binding of either the CXC-chemokine, stromal-derived factor 1α (SDF-1α), or a CXCR4 antagonist, AMD3100, to CXCR4 inhibits infection of CD4⁺ T cells by T-tropic HIV-1, although only SDF-1α triggers T-cell signaling cascades. We have previously demonstrated that ligation of CD4 by T-cell tropic HIV-1 NL4-3 induces metalloproteinase-dependent L-selectin (CD62L) shedding on resting CD4⁺ T cells. However, the role of CXCR4 in HIV-induced L-selectin shedding is unclear. Here, we show that L-selectin shedding induced by HIV-1 NL4-3 is completely reversed by AMD3100, but not SDF-1α, although SDF-1α alone does not induce L-selectin shedding. These results indicate that engagement of both CD4 and CXCR4 is required for HIV-induced shedding of L-selectin on primary resting CD4⁺ T cells.

Groundbreaking research has led to an understanding of some of the pathogenic mechanisms of HIV-1 infection. Surprisingly, an unanswered question remains the mechanism(s) by which HIV-1 inactivates or kills T cells. Our goals are to define candidate T cell signaling cascades altered by HIV infection and to identify mechanisms whereby HIV-infected cells escape the apoptosis triggered by this aberrant signaling. In earlier work, we found that HIV reprograms healthy T cells to self-destruct by a process called apoptosis. We asked whether apoptosis occurs in organs of infected people and made a surprising discovery-this cell death occurs predominantly in healthy bystander cells and only rarely in infected cells. We hypothesize that HIV may be doubly diabolical-healthy T cells are killed in HIV infection, while infected cells resist killing. Thus, the virus protects its viral factory and allows HIV to turn the cell into a "Trojan Horse," with the virus in hiding or "latent." In this review, we discuss the role of viral and cellular proteins in HIV induced T cell anergy and death. We also discuss mechanisms by which HIV may protect infected T cells from apoptosis. These studies will yield new insights into the pathogenesis of AIDS, identify cellular targets that regulate HIV-1 infection, and suggest novel therapeutic approaches to cure HIV infection.

At present, treatment of HIV infection uses small inhibitory molecules that target HIV protease; however, the emergence of resistant HIV strains is increasingly problematic. To circumvent this, we report here a new ‘Trojan horse' strategy to kill HIV-infected cells by exploiting HIV protease. We engineered a transducing, modified, apoptosis-promoting caspase-3 protein, TAT–Casp3, that substitutes HIV proteolytic cleavage sites for endogenous ones and efficiently transduces about 100% of cells, but remains inactive in uninfected cells. In HIV-infected cells, TAT–Casp3 becomes processed into an active form by HIV protease, resulting in apoptosis of the infected cell. This strategy could also be applied to other pathogens encoding specific proteases, such as hepatitis C virus, cytomegalovirus and malaria.

We have studied apoptosis in lymph node and peripheral blood mononuclear cells (PBMCs) from HIV-infected children and adults and SIV-infected rhesus macaques. In lymph nodes, we found that apoptosis and productive infection occurred only rarely in the same cell. There was, however, a direct correlation between the numbers of apoptotic and productively-infected cells. In HIV-infected children, we found a direct correlation between disease severity and percentage CD4+ T cell apoptosis (p = 0.001). Both CD4+ and CD8+ T cell apoptosis were directly related to CD4+ T cell depletion (p = 0.006 and p = 0.01, respectively). In addition, we found a trend towards diminished CD4+ T cell apoptosis on anti-retroviral agents. These findings suggest that apoptosis of uninfected cells may be important in HIV pathogenesis and that measurement of apoptosis may be a useful marker of disease activity.