Jiyeon S. Kim

Asymmetric Proteasome Segregation as a Mechanism for Unequal Partitioning of the Transcription Factor T-bet during T Lymphocyte Division

Polarized segregation of proteins in T cells is thought to play a role in diverse cellular functions including signal transduction, migration, and directed secretion of cytokines. Persistence of this polarization can result in asymmetric segregation of fate-determining proteins during cell division, which may enable a T cell to generate diverse progeny. Here, we provide evidence that a lineage-determining transcription factor, T-bet, underwent asymmetric organization in activated T cells preparing to divide and that it was unequally partitioned into the two daughter cells. This unequal acquisition of T-bet appeared to result from its asymmetric destruction during mitosis by virtue of concomitant asymmetric segregation of the proteasome. These results suggest a mechanism by which a cell may unequally localize cellular activities during division, thereby imparting disparity in the abundance of cell fate regulators in the daughter cells.

Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways

Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt plays a critical role in regulating nTH17 cell development. While Akt and the downstream mTORC1–ARNT–HIFα axis were required for inducible TH17 (iTH17) cell generation in the periphery, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for nTH17 cell development. Moreover, Akt controlled TH17 subsets through distinct isoforms, as deletion of Akt2, but not Akt1, led to defective iTH17 cell generation. These findings reveal novel mechanisms regulating nTH17 cell development and previously unknown roles of Akt and mTOR in shaping T cell subsets.Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1–ARNT–HIFα axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.

T-cell receptor signals direct the composition and function of the memory CD8+ T-cell pool.

SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) nucleates a signaling complex critical for T-cell receptor (TCR) signal propagation. Mutations in the tyrosines of SLP-76 result in graded defects in TCR-induced signals depending on the tyrosine(s) affected. Here we use 2 strains of genomic knock-in mice expressing tyrosine to phenylalanine mutations to examine the role of TCR signals in the differentiation of effector and memory CD8(+) T cells in response to infection in vivo. Our data support a model in which altered TCR signals can determine the rate of memory versus effector cell differentiation independent of initial T-cell expansion. Furthermore, we show that TCR signals sufficient to promote CD8(+) T-cell differentiation are different from those required to elicit inflammatory cytokine production.

Requirements for Eomesodermin and Promyelocytic Leukemia Zinc Finger in the Development of Innate-Like CD8+ T Cells

Conventional and nonconventional T cell development occur in the thymus. Nonconventional thymocytes that bear characteristics typically associated with innate immune cells are termed innate-like lymphocytes (ILLs). Mice harboring a tyrosine to phenylalanine mutation in the adaptor protein Src homology 2 domain-containing leukocyte protein of 76 kDa at residue 145 (Y145F mice) develop an expanded population of CD8+CD122+CD44+ ILLs, typified by expression of the T-box transcription factor eomesodermin. Y145F mice also have an expanded population of γδ T cells that produce copious amounts of IL-4 via a mechanism that is dependent on the BTB-ZF transcription factor promyelocytic leukemia zinc finger. Using mice with T cell-specific deletion of Eomes, we demonstrate that this transcription factor is required for CD8+ ILL development in Y145F as well as wild-type mice. Moreover, we show that promyelocytic leukemia zinc finger and IL-4 are also required for the generation of this ILL population. Taken together, these data shed light on the cell-intrinsic and cell-extrinsic factors that drive CD8+ ILL differentiation.

The requirements for natural Th17 cell development are distinct from those of conventional Th17 cells

A distinct population of Th17 cells develops in the thymus with innate immune cell characteristics, different selection requirements, and skewed TCR gene usage compared with peripheral Th17 cells.

Diversity of IL-17-producing T lymphocytes

Interleukin (IL)-17 is a pro-inflammatory cytokine that plays critical roles in host defense against extracellular bacteria and fungi and also in the pathogenesis of autoimmune diseases. While CD4+ TCRαβ+ T helper (Th) 17 cells are the best-described cellular source of IL-17, many innate-like T cells are in fact potent producers of IL-17. Given the increasing interest in therapeutic modulation of the IL-17 axis, it is crucial to better understand the cellular origins of IL-17 in various infection and diseases settings. While the diverse population of IL-17-producing T cells share many common characteristics, notable differences also exist. In this review, we discuss the heterogeneity of IL-17-producing T cell types focusing on their development, regulation, and function.

Site-specific accumulation of recently activated CD4+Foxp3+ regulatory T cells following adoptive transfer

CD4+Foxp3+ regulatory T (Treg) cells are required for the maintenance of self‐tolerance, as demonstrated by profound autoimmunity in mice and humans with inactivating Foxp3 mutations. Recent studies demonstrate that Treg cells are anatomically compartmentalized within secondary lymphoid organs based on their TCR repertoire and specific organ‐protective function; however, whether this reflects differential homing or in situ selection is not known. Here, using Foxp3‐GFP reporter mice, we have examined the ability of polyclonal Treg cells from cervical LNs to return to their site‐of‐origin following adoptive transfer to nonlymphopenic congenic recipients. We find that bulk cervical LN Treg cells do not home directly to cervical LNs but rather accumulate site specifically over time following transfer. Site‐specific enrichment is both more rapid and more pronounced among a population of recently activated (CD69+) Treg cells. These data suggest that compartmentalization of Treg cells within secondary lymphoid organs may be governed by antigen recognition and implicate CD69 as a potential marker of recently activated Treg cells recognizing locally expressed antigens.

SLP-76 is required for optimal CXCR4-stimulated T lymphocyte firm arrest to ICAM-1 under shear flow

Rapid arrest of T cells at target sites upon engagement of chemokine receptors is crucial to the proper functioning of the immune system. Although T‐cell arrest always occurs under hydrodynamic forces in vivo, most studies investigating the molecular mechanisms of arrest have been performed under static conditions. While the requirement of the adapter protein SLP‐76 (Src homology 2‐domain containing leukocyte‐specific phosphoprotein of 76 kDa) in TCR‐induced integrin activation has been demonstrated, its role in chemokine‐triggered T‐cell adhesion is unknown. Using a flow chamber system, we show that SLP‐76 plays an important role in regulating the transition from tethering and rolling to firm adhesion of T cells under physiological shear flow in response to CXCL12α (stromal cell‐derived factor‐1α); SLP‐76‐deficient primary T cells exhibited defective adhesion with a significant decrease in the number of firmly arrested cells. We further demonstrate the N‐terminal phosphotyrosines of SLP‐76 play a critical role in T‐cell adhesion under flow. These findings reveal a novel role for SLP‐76 in CXCR4‐mediated T lymphocyte trafficking.

Retraction: Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways.

Nat. Immunol. 14, 611–618 (2013); published online 5 May 2013 We are retracting this publication due to the discovery by the authors that some of the results presented in the paper are unsupported. We deeply regret this circumstance and apologize for any adverse consequences that this might have forthe scientific community.

Src Homology 2-Domain Containing Leukocyte-Specific Phosphoprotein of 76 kDa (SLP-76) Is Required for Optimal CXCR4-Stimulated T Lymphocyte Firm Arrest to ICAM-1 Under Shear Flow

Rapid arrest of T cells at target sites upon engagement of chemokine receptors is crucial to the proper functioning of the immune system. Although T‐cell arrest always occurs under hydrodynamic forces in vivo, most studies investigating the molecular mechanisms of arrest have been performed under static conditions. While the requirement of the adapter protein SLP‐76 (Src homology 2‐domain containing leukocyte‐specific phosphoprotein of 76 kDa) in TCR‐induced integrin activation has been demonstrated, its role in chemokine‐triggered T‐cell adhesion is unknown. Using a flow chamber system, we show that SLP‐76 plays an important role in regulating the transition from tethering and rolling to firm adhesion of T cells under physiological shear flow in response to CXCL12α (stromal cell‐derived factor‐1α); SLP‐76‐deficient primary T cells exhibited defective adhesion with a significant decrease in the number of firmly arrested cells. We further demonstrate the N‐terminal phosphotyrosines of SLP‐76 play a critical role in T‐cell adhesion under flow. These findings reveal a novel role for SLP‐76 in CXCR4‐mediated T lymphocyte trafficking.