Exposing T Cell Secrets Inside and Outside the Thymus.

I've had serious misgivings about writing this article, because from living the experience day by day, it's hard to believe my accomplishments merit the attention. To skirt this roadblock, I forced myself to pretend I was in a conversation with my trainees, trying to distill the central driving forces of my career in science. The below chronicles my evolution from would-be astronaut/ballerina to budding developmental biologist to devoted T cell immunologist.

Androgen Receptors in Epithelial Cells Regulate Thymopoiesis and Recent Thymic Emigrants in Male Mice.

Androgens have profound effects on T cell homeostasis, including regulation of thymic T lymphopoiesis (thymopoiesis) and production of recent thymic emigrants (RTEs), i. e., immature T cells that derive from the thymus and continue their maturation to mature naïve T cells in secondary lymphoid organs.

Cutting Edge: Glycolytic Metabolism and Mitochondrial Metabolism Are Uncoupled in Antigen-Activated CD8 Recent Thymic Emigrants.

Recent thymic emigrants (RTEs) are peripheral T cells that have most recently completed selection and thymic egress and constitute a population that is phenotypically and functionally distinct from its more mature counterpart. Ag-activated RTEs are less potent effectors than are activated mature T cells, due in part to reduced aerobic glycolysis (correctable by exogenous IL-2), which in turn impacts IFN-γ production. Mitochondria serve as nodal regulators of cell function, but their contribution to the unique biology of RTEs is unknown.

Reinterpreting recent thymic emigrant function: defective or adaptive?

Recent thymic emigrants (RTEs) are those peripheral T cells that have most recently completed thymic development and egress. Over the past decade, significant advances have been made in understanding the cell-extrinsic and cell-intrinsic requirements for RTE maturation to mature naïve (MN) T cells and in detailing the functional differences that characterize these two T cell populations. Much of this work has suggested that RTEs are hypo-functional versions of more mature T cells.

Cutting Edge: Defective Aerobic Glycolysis Defines the Distinct Effector Function in Antigen-Activated CD8 Recent Thymic Emigrants.

Recent thymic emigrants (RTEs) are the youngest peripheral T cells that have completed thymic selection and egress to the lymphoid periphery. RTEs are functionally distinct from their more mature but still naive T cell counterparts, because they exhibit dampened proliferation and reduced cytokine production upon activation. In this article, we show that, compared with more mature but still naive T cells, RTEs are impaired in their ability to perform aerobic glycolysis following activation.

Local Inflammatory Cues Regulate Differentiation and Persistence of CD8 Tissue-Resident Memory T Cells.

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 CD103CD69 Trm subset. Intestinal proinflammatory microenvironments have elevated interferon (IFN)-β and interleukin-12 (IL-12), which regulated Trm markers, including CD103.

Recent thymic emigrants are tolerized in the absence of inflammation.

T cell development requires a period of postthymic maturation. Why this is the case has remained a mystery, particularly given the rigors of intrathymic developmental checkpoints, successfully traversed by only ∼5% of thymocytes. We now show that the first few weeks of T cell residence in the lymphoid periphery define a period of heightened susceptibility to tolerance induction to tissue-restricted antigens (TRAs), the outcome of which depends on the context in which recent thymic emigrants (RTEs) encounter antigen.

Cutting Edge: Enhanced Clonal Burst Size Corrects an Otherwise Defective Memory Response by CD8+ Recent Thymic Emigrants.

The youngest peripheral T cells (recent thymic emigrants [RTEs]) are functionally distinct from naive T cells that have completed postthymic maturation. We assessed the RTE memory response and found that RTEs produced less granzyme B than their mature counterparts during infection but proliferated more and, therefore, generated equivalent target killing in vivo. Postinfection, RTE numbers contracted less dramatically than those of mature T cells, but RTEs were delayed in their transition to central memory, displaying impaired expression of CD62L, IL-2, Eomesodermin, and CXCR4, which resulted in impaired bone marrow localization.

ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis.

Immune control of persistent infection with Mycobacterium tuberculosis (Mtb) requires a sustained pathogen-specific CD4 T cell response; however, the molecular pathways governing the generation and maintenance of Mtb protective CD4 T cells are poorly understood. Using MHCII tetramers, we show that Mtb-specific CD4 T cells are subject to ongoing antigenic stimulation. Despite this chronic stimulation, a subset of PD-1(+) cells is maintained within the lung parenchyma during tuberculosis (TB).

Evaluation of approaches to monitor Staphylococcus aureus virulence factor expression during human disease.

Staphylococcus aureus is a versatile pathogen of medical significance, using multiple virulence factors to cause disease. A prophylactic S. aureus 4-antigen (SA4Ag) vaccine comprising capsular polysaccharide (types 5 and 8) conjugates, clumping factor A (ClfA) and manganese transporter C (MntC) is under development.

Heme exporter FLVCR is required for T cell development and peripheral survival.

All aerobic cells and organisms must synthesize heme from the amino acid glycine and the tricarboxylic acid cycle intermediate succinyl CoA for incorporation into hemoproteins, such as the cytochromes needed for oxidative phosphorylation. Most studies on heme regulation have been done in erythroid cells or hepatocytes; however, much less is known about heme metabolism in other cell types. The feline leukemia virus subgroup C receptor (FLVCR) is a 12-transmembrane domain surface protein that exports heme from cells, and it was shown to be required for erythroid development.

Cutting edge: CD8+ recent thymic emigrants exhibit increased responses to low-affinity ligands and improved access to peripheral sites of inflammation.

To explore the TCR sensitivity of recent thymic emigrants (RTEs), we triggered T cells with altered peptide ligands (APLs). Upon peptide stimulation in vitro, RTEs exhibited increased TCR signal transduction, and following infection in vivo with APL-expressing bacteria, CD8 RTEs expanded to a greater extent in response to low-affinity Ags than did their mature T cell counterparts. RTEs skewed to short-lived effector cells in response to all APLs but also were characterized by diminished cytokine production.

Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions.

Peripheral CD4 T cells in Vβ5 transgenic (Tg) C57BL/6J mice undergo tolerance to an endogenous superantigen encoded by mouse mammary tumor virus 8 (Mtv-8) by either deletion or T-cell receptor (TCR) revision. Revision is a process by which surface expression of the Vβ5(+) TCR is down-regulated in response to Mtv-8 and recombination activating genes are expressed to drive rearrangement of the endogenous TCRβ locus, effecting cell rescue through the expression of a newly generated, non-self-reactive TCR. In an effort to identify the microenvironment in which revision takes place, we show here that the proportion of T follicular helper cells (Tfh) and production of high-affinity antibody during a primary response are increased in Vβ5 Tg mice in an Mtv-8-dependent manner.

The ribosomal protein Rpl22 controls ribosome composition by directly repressing expression of its own paralog, Rpl22l1.

Most yeast ribosomal protein genes are duplicated and their characterization has led to hypotheses regarding the existence of specialized ribosomes with different subunit composition or specifically-tailored functions. In yeast, ribosomal protein genes are generally duplicated and evidence has emerged that paralogs might have specific roles. Unlike yeast, most mammalian ribosomal proteins are thought to be encoded by a single gene copy, raising the possibility that heterogenous populations of ribosomes are unique to yeast.

Immune vulnerability of infants to tuberculosis.

One of the challenges faced by the infant immune system is learning to distinguish the myriad of foreign but nonthreatening antigens encountered from those expressed by true pathogens. This balance is reflected in the diminished production of proinflammatory cytokines by both innate and adaptive immune cells in the infant. A downside of this bias is that several factors critical for controlling Mycobacterium tuberculosis infection are significantly restricted in infants, including TNF, IL-1, and IL-12.

Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci.

Recent thymic emigrants (RTEs) are the youngest T cells in the lymphoid periphery and exhibit phenotypic and functional characteristics distinct from those of their more mature counterparts in the naive peripheral T cell pool. We show in this study that the Il2 and Il4 promoter regions of naive CD4(+) RTEs are characterized by site-specific hypermethylation compared with those of both mature naive (MN) T cells and the thymocyte precursors of RTEs. Thus, RTEs do not merely occupy a midpoint between the thymus and the mature T cell pool, but represent a distinct transitional T cell population.

Capsular polysaccharides are an important immune evasion mechanism for Staphylococcus aureus.

Staphylococcus aureus can cause severe life threatening invasive diseases. The principal immune effector mechanism by which humans are protected from Gram positive bacteria such as S. aureus is antigen specific antibody- and complement-dependent opsonophagocytosis.

The biology of recent thymic emigrants.

The generation of the TCRαβ lineage of T cells occurs in the thymus through a series of orchestrated developmental events that result in a carefully selected population of CD4 or CD8 lineage-committed TCR(+) thymocytes capable of recognizing foreign antigen in the context of self MHC. T cells first exit the thymus in a phenotypically and functionally immature state and require an approximately 3-week period of post-thymic maturation before transitioning into the mature T cell compartment. A greater understanding of recent thymic emigrant biology has come with the development of methods to exclusively identify and isolate this population for further characterization.

Thymus-autonomous T cell development in the absence of progenitor import.

Thymus function is thought to depend on a steady supply of T cell progenitors from the bone marrow. The notion that the thymus lacks progenitors with self-renewal capacity is based on thymus transplantation experiments in which host-derived thymocytes replaced thymus-resident cells within 4 wk. Thymus grafting into T cell-deficient mice resulted in a wave of T cell export from the thymus, followed by colonization of the thymus by host-derived progenitors, and cessation of T cell development.

Homeostatic signals do not drive post-thymic T cell maturation.

Recent thymic emigrants, the youngest T cells in the lymphoid periphery, undergo a 3 week-long period of functional and phenotypic maturation before being incorporated into the pool of mature, naïve T cells. Previous studies indicate that this maturation requires T cell exit from the thymus and access to secondary lymphoid organs, but is MHC-independent. We now show that post-thymic T cell maturation is independent of homeostatic and costimulatory pathways, requiring neither signals delivered by IL-7 nor CD80/86.