I develop a graph-theoretic model theory for pure and iterative grounding logics.

The present paper discusses the treatment of diagrammatic proof in Schopenhauer’s philosophy of mathematics. ‘Picture proofs’ have been the subject of some scattered contemporary debate, and my aim here is to see whether Schopenhauer’s treatment might prove fruitful in the context of recent discussion. In particular I argue that Schopenhauer’s remarks on diagrammatic proof, though few and far between, might be able to provide conceptual tools adequate to meet some of the broader challenges facing the legitimacy of such proof. In § 1 the notion of a picture proof is introduced and two general objections to its legitimacy are formulated. In § 2 I set out what I take to be the substance of Schopenhauer’s advocacy of picture proofs and in § 3 I formulate replies to these challenges based on the Schopenhauerian distinction between a proposition’s ground of knowledge (Erkenntnißgrund) and its ground of being (Seynsgrund).

Several years ago Doherty and Zinkernagel reported experiments that seemed to be paradoxical within the classical theoretical framework of clonal selection: "one lymphocyte, one specific receptor". Current biochemical work suggests that that old paradigm is quite remarkably resilient. But Peter Doherty sees serious, unresolved problems.

ABSTRACT The mouse model of West Nile virus (WNV), which is a leading cause of mosquito-borne encephalitis worldwide, has provided fundamental insights into the host and viral factors that regulate viral pathogenesis and infection outcome. In particular, CD8+ T cells are critical for controlling WNV replication and promoting protection against infection. Here, we present the characterization of a T cell receptor (TCR)-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein (here referred to as transgenic WNV-I mice). Using an adoptive-transfer model, we found that WNV-I CD8+ T cells behave similarly to endogenous CD8+ T cell responses, with an expansion phase in the periphery beginning around day 7 postinfection (p.i.) followed by a contraction phase through day 15 p.i. Through the use of in vivo intravascular immune cell staining, we determined the kinetics, expansion, and differentiation into effector and memory subsets of WNV-I CD8+ T cells within the spleen and brain. We found that red-pulp WNV-I CD8+ T cells were more effector-like than white-pulp WNV-I CD8+ T cells, which displayed increased differentiation into memory precursor cells. Within the central nervous system (CNS), we found that WNV-I CD8+ T cells were polyfunctional (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), displayed tissue-resident characteristics (CD69+ and CD103+), persisted in the brain through day 15 p.i., and reduced the viral burden within the brain. The use of these TCR-transgenic WNV-I mice provides a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection. IMPORTANCE West Nile Virus (WNV) is the leading cause of mosquito-borne encephalitis worldwide. There are currently no approved therapeutics or vaccines for use in humans to treat or prevent WNV infection. CD8+ T cells are critical for controlling WNV replication and protecting against infection. Here, we present a comprehensive characterization of a novel TCR-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein. In this study, we determine the kinetics, proliferation, differentiation into effector and memory subsets, homing, and clearance of WNV in the CNS. Our findings provide a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection.

Many pathogens initiate infection at mucosal surfaces, and tissue-resident memory T (Trm) cells play an important role in protective immunity, yet the tissue-specific signals that regulate Trm differentiation are poorly defined. During Yersinia infection, CD8+ T cell recruitment to areas of inflammation within the intestine is required for differentiation of the CD103−CD69+ Trm subset. Intestinal proinflammatory microenvironments have elevated interferon (IFN)-β and interleukin-12 (IL-12), which regulated Trm markers, including CD103. Type I interferon-receptor- or IL-12-receptor-deficient T cells functioned similarly to wild-type (WT) cells during infection; however, the inability of T cells to respond to inflammation resulted in defective differentiation of CD103−CD69+ Trm cells and reduced Trm persistence. Intestinal macrophages were the main producers of IFN-β and IL-12 during infection, and deletion of CCR2+ IL-12-producing cells reduced the size of the CD103− Trm population. These data indicate that intestinal inflammation drives phenotypic diversity and abundance of Trm cells for optimal tissue-specific immunity.

The study of T cell immunity at barrier surfaces has largely focused on T cells bearing the αβ TCR. However, T cells that express the γδ TCR are disproportionately represented in peripheral tissues of mice and humans, suggesting they too may play an important role responding to external stimuli. In this article, we report that, in a murine model of cutaneous infection with vaccinia virus, dermal γδ T cell numbers increased 10-fold in the infected ear and resulted in a novel γδ T cell population not found in naive skin. Circulating γδ T cells were specifically recruited to the site of inflammation and differentially contributed to dermal populations based on their CD27 expression. Recruited γδ T cells, the majority of which were CD27+, were granzyme B+ and made up about half of the dermal population at the peak of the response. In contrast, recruited and resident γδ T cell populations that made IL-17 were CD27−. Using a double-chimera model that can discriminate between the resident dermal and recruited γδ T cell populations, we demonstrated their divergent functions and contributions to early stages of tissue inflammation. Specifically, the loss of the perinatal thymus-derived resident dermal population resulted in decreased cellularity and collateral damage in the tissue during viral infection. These findings have important implications for our understanding of immune coordination at barrier surfaces and the contribution of innate-like lymphocytes on the front lines of immune defense.

Tissue-resident memory T cells (TRM cells) provide rapid frontline protection from reinfection. Bergsbaken and Bevan identify a gut TRM cell population generated via an unconventional pathway that is protective against a natural mouse intestinal pathogen. We report that oral infection with Yersinia pseudotuberculosis results in the development of two distinct populations of pathogen-specific CD8+ tissue-resident memory T cells (TRM cells) in the lamina propria. CD103− T cells did not require transforming growth factor-β (TGF-β) signaling but were true resident memory cells. Unlike CD103+CD8+ T cells, which were TGF-β dependent and were scattered in the tissue, CD103−CD8+ T cells clustered with CD4+ T cells and CX3CR1+ macrophages and/or dendritic cells around areas of bacterial infection. CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103− population and pathogen clearance. Our studies have identified the 'preferential' development of CD103− TRM cells in inflammatory microenvironments within the lamina propria and suggest that this subset has a critical role in controlling infection.

Inflammatory caspases, including caspase-11, are upregulated in CD8+ T cells after Ag-specific activation, but little is known about their function in T cells. We report that caspase-11–deficient (Casp11−/−) T cells proliferated more readily in response to low-affinity and low-abundance ligands both in vitro and in vivo due to an increased ability to signal through the TCR. In addition to increased numbers, Casp11−/− T cells had enhanced effector function compared with wild-type cells, including increased production of IL-2 and reduced expression of CD62L. Casp11−/− T cells specific for endogenous Ags were more readily deleted than wild-type cells. These data indicate that caspase-11 negatively regulates TCR signaling, possibly through its ability to regulate actin polymerization, and inhibiting its activity could enhance the expansion and function of low-affinity T cells.

We used a newly generated T-cell receptor mimic monoclonal antibody (TCRm MAb) that recognizes a known nonself immunodominant peptide epitope from West Nile virus (WNV) NS4B protein to investigate epitope presentation after virus infection in C57BL/6 mice. Previous studies suggested that peptides of different length, either SSVWNATTAI (10-mer) or SSVWNATTA (9-mer) in complex with class I MHC antigen H-2D(b) , were immunodominant after WNV infection. Our data establish that both peptides are presented on the cell surface after WNV infection and that CD8(+) T cells can detect 10- and 9-mer length variants similarly. This result varies from the idea that a given T-cell receptor (TCR) prefers a single peptide length bound to its cognate class I MHC. In separate WNV infection studies with the TCRm MAb, we show that in vivo the 10-mer was presented on the surface of uninfected and infected CD8α(+) CD11c(+) dendritic cells, which suggests the use of direct and cross-presentation pathways. In contrast, CD11b(+) CD11c(-) cells bound the TCRm MAb only when they were infected. Our study demonstrates that TCR recognition of peptides is not limited to certain peptide lengths and that TCRm MAbs can be used to dissect the cell-type specific mechanisms of antigen presentation in vivo.

A hallmark of immunological memory is the ability of previously primed T cells to undergo rapid recall responses upon antigen reencounter. Classic work has suggested that memory T cells proliferate in response to lower doses of antigen than naive T cells and with reduced requirements for co-stimulation. In contrast to this premise, we observed that naive but not memory T cells proliferate in vivo in response to limited antigen presentation. To reconcile these observations, we tested the antigen threshold requirement for cell cycle entry in naive and central memory CD8(+) T cells. Although both naive and memory T cells detect low dose antigen, only naive T cells activate cell cycle effectors. Direct comparison of TCR signaling on a single cell basis indicated that central memory T cells do not activate Zap70, induce cMyc expression, or degrade p27 in response to antigen levels that activate these functions in naive T cells. The reduced sensitivity of memory T cells may result from both decreased surface TCR expression and increased expression of protein tyrosine phosphatases as compared with naive T cells. Our data describe a novel aspect of memory T cell antigen threshold sensitivity that may critically regulate recall expansion.

Significance Identifying factors that regulate the development of cytokine-producing immunoregulatory invariant natural killer T (iNKT) cells is critical for understanding how to modulate these cells to promote cell-mediated immunity to cancer and infectious organisms or suppress excessive inflammation in autoimmune disease. Here, we identified an essential role for the metabolic regulator Folliculin-interacting protein 1 (Fnip1) in iNKT cell development and survival. Fnip1 physically interacts with AMPK, an energy-sensing enzyme that stimulates mitochondria and ATP production in response to energy deficit, while inhibiting mammalian target of rapamycin (mTOR)-mediated cell growth. Fnip1-deficient iNKT cells contain reduced mitochondrial number and hyperactive mTOR, which resulted in decreased ATP levels and increased sensitivity to apoptosis. Our findings indicate that Fnip1 is vital for maintaining metabolic balance during iNKT cell development.

Generating a diverse T cell memory population through vaccination is a promising strategy to overcome pathogen epitope variability and tolerance to tumor Ags. The effector and memory pool becomes broad in TCR diversity by recruiting high- and low-affinity T cells. We wanted to determine which factors dictate whether a memory T cell pool has a broad versus focused repertoire. We find that inflammation increases the magnitude of low-and high-affinity T cell responses equally well, arguing against a synergistic effect of TCR and inflammatory signals on T cell expansion. We dissect the differential effects of TCR signal strength and inflammation and demonstrate that they control effector T cell survival in a bim-dependent manner. Importantly, bim-dependent cell death is overcome with a high Ag dose in the context of an inflammatory environment. Our data define the framework for the generation of a broad T cell memory pool to inform future vaccine design.

West Nile Virus (WNV) is an RNA virus that is the leading cause of mosquito-borne encephalitis in the United States. Recently, we demonstrated that MAVS, the central adaptor molecule of the RIG-I like receptor (RLR) signaling pathway, is essential role in programming innate and adaptive immune defenses to control WNV infection. However, the role of the individual RLRs in directing immunity during virus infection has not been clearly defined. WNV infection of Lgp2-/- mice showed increased mortality which corresponded to enhanced virus replication and reduced antigen-specific CD8+ T cells in the CNS at late times during infection. While LGP2 was determined to be non-essential in innate immune responses to WNV infection, LGP2 was required for controlling antigen-specific CD8+ T cell survival and effector functions during virus infection. Adoptive transfer studies of WT and Lgp2-/- CD8+ T cells into Rag-/- mice demonstrated that LGP2 functions in a cell-intrinsic manner to regulate T cell sensitivity to CD95-mediated cell death. Biochemical studies showed that LGP2 expression in CD8+ T cells is regulated through crosstalk between the T cell receptor signaling and interferon signaling pathways. Mechanisms by which LGP2 regulates extrinsic apoptosis signaling and T cell survival will be discussed. Overall, these studies demonstrate a novel for LGP2 in regulating T cell immunity and reveals a broader role for RLRs in programming adaptive immune responses during virus infection.

During an infection the antigen-nonspecific memory CD8 T cell compartment is not simply an inert pool of cells, but becomes activated and cytotoxic. It is unknown how these cells contribute to the clearance of an infection. We measured the strength of T cell receptor (TCR) signals that bystander-activated, cytotoxic CD8 T cells (BA-CTLs) receive in vivo and found evidence of limited TCR signaling. Given this marginal contribution of the TCR, we asked how BA-CTLs identify infected target cells. We show that target cells express NKG2D ligands following bacterial infection and demonstrate that BA-CTLs directly eliminate these target cells in an innate-like, NKG2D-dependent manner. Selective inhibition of BA-CTL-mediated killing led to a significant defect in pathogen clearance. Together, these data suggest an innate role for memory CD8 T cells in the early immune response before the onset of a de novo generated, antigen-specific CD8 T cell response.