The partitioning of TCR repertoires by thymic selection.

αβ T cells are critical components of the adaptive immune system; they maintain tissue and immune homeostasis during health, provide sterilizing immunity after pathogen infection, and are capable of eliminating transformed tumor cells. Fundamental to these distinct functions is the ligand specificity of the unique antigen receptor expressed on each mature T cell (TCR), which endows lymphocytes with the ability to behave in a cell-autonomous, disease context-specific manner. Clone-specific behavioral properties are initially established during T cell development when thymocytes use TCR recognition of major histocompatibility complex (MHC) and MHC-like ligands to instruct survival versus death and to differentiate into a plethora of inflammatory and regulatory T cell lineages.

How persistent infection overcomes peripheral tolerance mechanisms to cause T cell-mediated autoimmune disease.

T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells.

CD4 Effector TCR Avidity for Peptide on APC Determines the Level of Memory Generated.

Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity.

I-A β56/57 polymorphisms regulate non-cognate negative selection to CD4 T cell orchestrators of type 1 diabetes.

Genetic susceptibility to type 1 diabetes is associated with homozygous expression of major histocompatibility complex class II alleles that carry specific beta chain polymorphisms. Why heterozygous expression of these major histocompatibility complex class II alleles does not confer a similar predisposition is unresolved. Using a nonobese diabetic mouse model, here we show that heterozygous expression of the type 1 diabetes-protective allele I-A β56P/57D induces negative selection to the I-A-restricted T cell repertoire, including beta-islet-specific CD4 T cells.

The perception and response of T cells to a changing environment are based on the law of initial value.

αβ T cells are critical components of the adaptive immune system and are capable of inducing sterilizing immunity after pathogen infection and eliminating transformed tumor cells. The development and function of T cells are controlled through the T cell antigen receptor, which recognizes peptides displayed on major histocompatibility complex (MHC) molecules. Here, we review how T cells generate the ability to recognize self-peptide-bound MHC molecules and use signals derived from these interactions to instruct cellular development, activation thresholds, and functional specialization in the steady state and during immune responses.

The curious case of a cryptic Cryptosporidium and a missing dendritic cell subset.

Animal models for studying immune responses to Cryptosporidium, a parasite that causes gastrointestinal disease, have been a challenge due to the parasite's poor infectivity in mice. Russler-Germain et al. discovered a 'commensal' strain of Cryptosporidium, capable of stable infection and vertical transmission, that elicits a T helper type 1 (Th1) response to promote intestinal homeostasis.

Resolving the Instructions for αβ T Cell Development.

In this issue of Immunity, Chopp et. al. use single-cell transcriptomics and epigenomics in mice and human samples to delineate developmental trajectories of αβ T cell subsets and refine the kinetic selection model of CD4 and CD8 T cell lineage commitment.

A temporal thymic selection switch and ligand binding kinetics constrain neonatal Foxp3 T cell development.

The neonatal thymus generates Foxp3 regulatory T (tT) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tT cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tT cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner.

Patients with mutations reveal a role for human CD3γ in T diversity and suppressive function.

Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, , , and gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, mutations lead to milder phenotypes, mainly characterized by autoimmunity.

Affinity for self antigen selects Treg cells with distinct functional properties.

The manner in which regulatory T cells (Treg cells) control lymphocyte homeostasis is not fully understood. We identified two Treg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes.

Hydrophobic CDR3 residues promote the development of self-reactive T cells.

Studies of individual T cell antigen receptors (TCRs) have shed some light on structural features that underlie self-reactivity. However, the general rules that can be used to predict whether TCRs are self-reactive have not been fully elucidated. Here we found that the interfacial hydrophobicity of amino acids at positions 6 and 7 of the complementarity-determining region CDR3β robustly promoted the development of self-reactive TCRs.

A "hotspot" for autoimmune T cells in type 1 diabetes.

The ability of a single T cell antigen receptor (TCR) to cross-react with multiple antigens allows the finite number of T cells within an organism to respond to the compendium of pathogen challenges faced during a lifetime. Effective immune surveillance, however, comes at a price. TCR cross-reactivity can allow molecular mimics to spuriously activate autoimmune T cells; it also underlies T cell rejection of organ transplants and drives graft-versus-host disease.

Role of T cell-glial cell interactions in creating and amplifying central nervous system inflammation and multiple sclerosis disease symptoms.

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System (CNS) that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons and axons. Historically, MS has been thought of as a T cell-mediated autoimmune disease of CNS white matter. However, recent studies have identified gray matter lesions in MS patients, suggesting that CNS antigens other than myelin proteins may be involved during the MS disease process.

Indoctrinating T cells to attack pathogens through homeschooling.

Adaptive immunity is predicated on the ability of the T cell repertoire to have pre-existing specificity for the universe of potential pathogens. Recent findings suggest that T cell receptor (TCR)-self-major histocompatibility protein (pMHC) interactions limit autoimmune responses while enhancing T cell response to foreign antigens. We review these findings here, placing them in context of the current understanding of how TCR-self-pMHC interactions regulate T cell activation thresholds, and suggest that TCR-self-pMHC interactions increase the efficiency of the T cell repertoire by giving a competitive advantage to peptide cross-reactive T cells.

Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance.

In the thymus, high-affinity, self-reactive thymocytes are eliminated from the pool of developing T cells, generating central tolerance. Here, we investigate how developing T cells measure self-antigen affinity. We show that very few CD4 or CD8 coreceptor molecules are coupled with the signal-initiating kinase, Lck.

Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation.

Cumulative T-cell receptor signal strength and ensuing T-cell responses are affected by both antigen affinity and antigen dose. Here we examined the distinct contributions of these parameters to CD4 T-cell differentiation during infection. We found that high antigen affinity positively correlates with T helper (Th)1 differentiation at both high and low doses of antigen.

Identifying environmental antigens that activate myelin-specific T cells.

Human genetic and environmental factors underlie susceptibility to the T cell-mediated autoimmune disease, multiple sclerosis (MS). How the environment influences the pathogenesis of MS has been difficult to parse. A recent paper in Cell shows that environmental antigens that activate myelin-specific T cells can be identified with unprecedented accuracy.

Effect of CDR3 sequences and distal V gene residues in regulating TCR-MHC contacts and ligand specificity.

The mature T cell repertoire has the ability to orchestrate immunity to a wide range of potential pathogen challenges. This ability stems from thymic development producing individual T cell clonotypes that express TCRs with unique patterns of Ag reactivity. The Ag specificity of TCRs is created from the combinatorial pairing of one of a set of germline encoded TCR Vα and Vβ gene segments with randomly created CDR3 sequences.

Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells.

Multiple sclerosis (MS) is an inflammatory disease of the CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons, and axons. Historically, MS has been thought to be a CD4 T cell-mediated autoimmune disease of CNS white matter. However, recent studies identified CD8 T cell infiltrates and gray matter lesions in MS patients.

Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection.

A naive CD4(+) T cell population specific for a microbial peptide:major histocompatibility complex II ligand (p:MHCII) typically consists of about 100 cells, each with a different T cell receptor (TCR). Following infection, this population produces a consistent ratio of effector cells that activate microbicidal functions of macrophages or help B cells make antibodies. We studied the mechanism that underlies this division of labor by tracking the progeny of single naive T cells.

Viral antigen density and confinement time regulate the reactivity pattern of CD4 T-cell responses to vaccinia virus infection.

T-cell recognition of ligands is polyspecific. This translates into antiviral T-cell responses having a range of potency and specificity for viral ligands. How these ligand recognition patterns are established is not fully understood.