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TCRαβ+ CD8α+CD8β–intestinal intraepithelial lymphocytes (CD8αα IEL) are gut T cells that maintain barrier surface homeostasis. Most CD8αα IEL are derived from thymic precursors (IELp) through a mechanism referred to as clonal diversion. In this model, self‐reactive thymocytes undergo deletion in the presence of CD28 costimulation, but in its absence undergo diversion to the IEL fate. While previous reports showed that IELp were largely β2m dependent, the APC that drive the development of these cells are poorly defined. We found that both CD80 and CD86 restrain IELp development, and conventional DCs play a prominent role. We sought to define a CD80/86 negative, MHCI positive APC that supports the development to the IEL lineage. Chimera studies showed that MHCI needs to be expressed on hematopoietic APC for selection. As thymic hematopoietic APC are heterogeneous in their expression of MHCI and costimulatory molecules, we identified four thymic APC types that were CD80/86neg/low and MHCI+. However, selective depletion of β2m in individual APC suggested functional redundancy. Thus, while hematopoietic APC play a critical role in clonal diversion, no single APC subset is specialized to promote the CD8αα IEL fate. [ABSTRACT FROM AUTHOR]

Summary Understanding the thymic processes that support the generation of functionally competent and self-tolerant lymphocytes requires dissection of the T-cell receptor (TCR) response to ligands of different affinities. In spatially segregated regions of the thymus, with unique expression of proteases and cytokines, TCR affinity guides a number of cell fate decisions. Yet affinity alone does not explain the selection paradox. Increasing evidence suggests that the 'altered peptide' model of the 1980s together with the affinity model might best explain how the thymus supports conventional and regulatory T-cell development. Development of new tools to study the strength of TCR signals perceived by T cells, novel regulatory T-cell transgenic mice, and tetramer enrichment strategies have provided an insight into the nature of TCR signals perceived during thymocyte development. These topics are discussed and support for the prevailing hypotheses is presented. [ABSTRACT FROM AUTHOR]

The thymus is a primary lymphoid organ supporting the development of self-tolerant T cells. Key events in T-cell development in the thymus include lineage commitment, selection events, and thymic emigration. This review discusses the proposed role of sphingosine-1-phosphate and its receptors in the emigration of both conventional and unconventional T-cell subsets from the thymus, and the molecular machinery currently understood to regulate this process. Furthermore, we highlight a role for chemokines and actin-associated proteins in T-cell motility as recent data suggest that T-cell emigration is regulated by more than just a sphingosine-1-phosphate receptor-1-dependent chemotactic axis. [ABSTRACT FROM AUTHOR]

The article offers information about Kruppellike factor 2 (KLF2) which are a large family of proteins that activate and repress genes and regulate various biological processes. It mentions that KLF2 is required for thymic emigration and lymph node homing. According to research findings, KLF2 coordinates expression of multiple types of cell surface receptors to control T-cell trafficking during an immune response. Also presented is a figure depicting KLF2 controlling T-cell trafficking.

Expression of tissue restricted antigens by lymph node stromal cells has been described, and results in T cell tolerance to self antigens. We have identified a model in which presentation of a skin antigen by non-hematopoietic cells induces autoimmunity. We employed K14-OVAp mice expressing an ovalbumin peptide in the epidermis to study CD8 T cell responses to a skin self antigen, and found that a radioresistant APC initiated a robust T cell response and autoimmunity. Langerhans cells (LC), the APC in the epidermis of the skin were the likely APC because they are radioresistant in hematopoietic chimeras. We addressed the same question in K14-mOVA mice, which express a transmembrane ovalbumin. In K14-mOVA mice, CD8 T cells became activated and divided, but did not expand or acquire effector function. In mice expressing both mOVA and OVAp transgenes, robust expansion occurred, suggesting that K14-mOVA antigen does not induce full immune activation or tolerance. Use of inducibly LC deficient K14-OVAp and K14-mOVA mice suggested that LC were dispensable for activation of T cells in both systems. Future experiments will identify the non-hematopoietic APC, and the mechanism behind K14-OVAp autoimmunity. [ABSTRACT FROM AUTHOR]

Our laboratory has identified the transcription factor Krüppel-like factor 2 (KLF2) as an important regulator of T cell migration. KLF2 deficient T cells mature normally but are retained in thymus. KLF2 controls the expression of receptors such as S1P1 and CD62L in T cells. The regulation of KLF2 expression in thymocytes is unknown. KLF2 is expressed late in single positive (SP) thymocyte development. We hypothesize a post-positive selection signal in semi-mature SPs thymocytes induces KLF2. The IL-7 receptor is down regulated in double positive (DP) thymocytes and expressed again after positive selection. Erk5 signaling has been implicated in KLF2 regulation in endothelial cells. We are testing the model that KLF2 expression depends on IL-7/Erk5 post-positive selection signaling. Comparing IL-7 receptor deficient to wild type mice, we find no difference between the KLF2 mRNA expression in sorted thymocytes. In addition, treatment with an IL-7 receptor blocking antibody does not affect thymic emigration. This data indicates that IL-7 signaling is not necessary for KLF2 expression. CD4-cre x Erk5 flox mice have been generated to test the effect of Erk5 deficiency in T cells. [ABSTRACT FROM AUTHOR]