CD5 expression by dendritic cells directs T cell immunity and sustains immunotherapy responses.

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1cCD5 DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy.

A RORγt cell instructs gut microbiota-specific T cell differentiation.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system.

Phase-variable bacteria simultaneously express multiple capsules.

Capsular polysaccharides (CPSs) protect bacteria from host and environmental factors. Many bacteria can express different CPSs and these CPSs are phase variable. For example, ) is a prominent member of the human gut microbiome and expresses eight different capsular polysaccharides.

Strength of tonic T cell receptor signaling instructs T follicular helper cell-fate decisions.

T follicular helper (T) cells are critical in adaptive immune responses to pathogens and vaccines; however, what drives the initiation of their developmental program remains unclear. Studies suggest that a T cell antigen receptor (TCR)-dependent mechanism may be responsible for the earliest T cell-fate decision, but a critical aspect of the TCR has been overlooked: tonic TCR signaling. We hypothesized that tonic signaling influences early T cell development.

Tonic TCR Signaling Inversely Regulates the Basal Metabolism of CD4 T Cells.

The contribution of self-peptide-MHC signaling in CD4 T cells to metabolic programming has not been definitively established. In this study, we employed LLO118 and LLO56, two TCRtg CD4 T cells that recognize the same epitope. We previously have shown that LLO56 T cells are highly self-reactive and respond poorly in a primary infection, whereas LLO118 cells, which are less self-reactive, respond well during primary infection.

Immunomodulatory Roles of Polysaccharide Capsules in the Intestine.

The interplay between the immune system and the microbiota in the human intestine dictates states of health vs. disease. Polysaccharide capsules are critical elements of bacteria that protect bacteria against environmental and host factors, including the host immune system.

Polysaccharide Capsules Equip the Human Symbiont to Modulate Immune Responses to a Dominant Antigen in the Intestine.

Bacteria express multiple diverse capsular polysaccharides (CPSs) for protection against environmental and host factors, including the host immune system. Using a mouse TCR transgenic CD4 T cell, BθOM, that is specific for and a complete set of single CPS-expressing strains, we ask whether CPSs can modify the immune responses to specific bacterial Ags. Acapsular , which lacks all CPSs, stimulated BθOM T cells more strongly than wild-type Despite similar levels of BθOM Ag expression, many single CPS-expressing strains were antistimulatory and weakly activated BθOM T cells, but a few strains were prostimulatory and strongly activated BθOM T cells just as well or better than an acapsular strain.

Diet modulates colonic T cell responses by regulating the expression of a antigen.

T cell responses to symbionts in the intestine drive tolerance or inflammation depending on the genetic background of the host. These symbionts in the gut sense the available nutrients and adapt their metabolic programs to use these nutrients efficiently. Here, we ask whether diet can alter the expression of a bacterial antigen to modulate adaptive immune responses.

Tropism for tuft cells determines immune promotion of norovirus pathogenesis.

Complex interactions between host immunity and the microbiome regulate norovirus infection. However, the mechanism of host immune promotion of enteric virus infection remains obscure. The cellular tropism of noroviruses is also unknown.

Tuning T Cell Signaling Sensitivity Alters the Behavior of CD4 T Cells during an Immune Response.

Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation of two TCR-transgenic CD4 T cell mouse lines, LLO56 and LLO118, which recognize the same cognate epitope with the same affinity.

LysMD3 is a type II membrane protein without an role in the response to a range of pathogens.

Germline-encoded receptors recognizing common pathogen-associated molecular patterns are a central element of the innate immune system and play an important role in shaping the host response to infection. Many of the innate immune molecules central to these signaling pathways are evolutionarily conserved. LysMD3 is a novel molecule containing a putative peptidoglycan-binding domain that has orthologs in humans, mice, zebrafish, flies, and worms.

The TCR Takes Some Immune Responsibility.

In this issue of Immunity, Van Braeckel-Budimmir et al. (2017) reveal that the pathogenic response of mice to a Plasmodium berghei infection is dominated by a Vβ8.1 T cell response.

Loss of Navβ4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance.

The resurgent component of voltage-gated Na (Nav) currents, I, has been suggested to provide the depolarizing drive for high-frequency firing and to be generated by voltage-dependent Nav channel block (at depolarized potentials) and unblock (at hyperpolarized potentials) by the accessory Navβ4 subunit. To test these hypotheses, we examined the effects of the targeted deletion of Scn4b (Navβ4) on I and on repetitive firing in cerebellar Purkinje neurons. We show here that Scn4b animals have deficits in motor coordination and balance and that firing rates in Scn4b Purkinje neurons are markedly attenuated.

Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival.

CLEC16A is in a locus genetically linked to autoimmune diseases including multiple sclerosis, but the function of this gene in the nervous system is unknown. Here we show that two mouse strains carrying independent Clec16a mutations developed neurodegenerative disease characterized by motor impairments and loss of Purkinje cells. Neurons from Clec16a-mutant mice exhibited increased expression of the autophagy substrate p62, accumulation of abnormal intra-axonal membranous structures bearing the autophagy protein LC3, and abnormal Golgi morphology.

Functional Heterogeneity in CD4(+) T Cell Responses Against a Bacterial Pathogen.

To investigate how CD4(+) T cells function against a bacterial pathogen, we generated a Listeria monocytogenes-specific CD4(+) T cell model. In this system, two TCRtg mouse lines, LLO56 and LLO118, recognize the same immunodominant epitope (LLO190-205) of L. monocytogenes and have identical in vitro responses.

Force-Regulated In Situ TCR-Peptide-Bound MHC Class II Kinetics Determine Functions of CD4+ T Cells.

We have recently shown that two-dimensional (2D) and force-regulated kinetics of TCR-peptide-bound MHC class I (pMHC-I) interactions predict responses of CD8(+) T cells. To test whether these findings are applicable to CD4(+) T cells, we analyzed the in situ 3.L2 TCR-pMHC-II interactions for a well-characterized panel of altered peptide ligands on the T cell surface using the adhesion frequency assay with a micropipette and the thermal fluctuation and force-clamp assays with a biomembrane force probe.

Colitogenic Bacteroides thetaiotaomicron Antigens Access Host Immune Cells in a Sulfatase-Dependent Manner via Outer Membrane Vesicles.

Microbes interact with the host immune system via several potential mechanisms. One essential step for each mechanism is the method by which intestinal microbes or their antigens access specific host immune cells. Using genetically susceptible mice (dnKO) that develop spontaneous, fulminant colitis, triggered by Bacteroides thetaiotaomicron (B.

Self-pMHCII complexes are variably expressed in the thymus and periphery independent of mRNA expression but dependent on the activation state of the APCs.

Self-peptide MHCII ligands are critical for selection of CD4+ T cells in the thymus, and maintenance in the periphery. To date, no investigation as to the exact thymic and peripheral expression of a naturally occurring positive selecting self-peptide MHCII (self-pMHCII) complex has taken place. We have generated a sensitive T cell hybridoma to functionally detect the endogenous presentation of a confirmed positive selecting self-pMHCII complex for a CD4+ transgenic T cell.

c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells.

Although the transcription factor c-Myc is essential for the establishment of a metabolically active and proliferative state in T cells after priming, its expression is transient. It remains unknown how T cell activation is maintained after c-Myc expression is downregulated. Here we identified AP4 as the transcription factor that was induced by c-Myc and sustained activation of antigen-specific CD8+ T cells.

Both positive and negative effects on immune responses by expression of a second class II MHC molecule.

It is perplexing why vertebrates express a limited number of major histocompatibility complex (MHC) molecules when theoretically, having a greater repertoire of MHC molecules would increase the number of epitopes presented, thereby enhancing thymic selection and T cell response to pathogens. It is possible that any positive effects would either be neutralized or outweighed by negative selection restricting the T cell repertoire. We hypothesize that the limit on MHC number is due to negative consequences arising from expressing additional MHC.

The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires.

Thymic selection is designed to ensure TCR reactivity to foreign Ags presented by self-MHC while minimizing reactivity to self-Ags. We hypothesized that the repertoire of T cells with unwanted specificities such as alloreactivity or autoreactivity are a consequence of simultaneous rearrangement of both TCRα loci. We hypothesized that this process helps maximize production of thymocytes capable of successfully completing thymic selection, but results in secondary TCRs that escape stringent selection.

Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see).

The fate of developing T cells is specified by the interaction of their antigen receptors with self-peptide-MHC complexes that are displayed by thymic antigen-presenting cells (APCs). Various subsets of thymic APCs are strategically positioned in particular thymic microenvironments and they coordinate the selection of a functional and self-tolerant T cell repertoire. In this Review, we discuss the different strategies that these APCs use to sample and process self antigens and to thereby generate partly unique, 'idiosyncratic' peptide-MHC ligandomes.