Development Of Αβ Research Articles

Development of αβ T Cells with Innate Functions.

Although we mostly think of αβ T cells as components of the adaptive immune system, a number of them differentiate into alternative lineages. These lineages express TCRs with limited diversity, and functionally bridge the gap between innate and adaptive immunity. They tend to be tissue resident, and mount potent cytokine responses very rapidly after activation, and their development and functional maturation are strongly influenced by the microbiome. Here, we compare the development pathways and interactions with the microbiome of natural killer T (NKT) cells and mucosal-associated invariant T (MAIT cells), the two best studied "innate-like" αβ T cell populations.

MicroRNA-181a/b-1 Is Not Required for Innate γδ NKT Effector Cell Development.

Thymic development of αβ T lymphocytes into invariant natural killer (NK) T cells depends on their selection via agonistic lipid antigen presented by CD1d. If successful, newly selected NKT cells gain effector functions already in the thymus. Some γδ T cell subsets also acquire effector functions in the thymus. However, it is not clear whether agonistic TCR stimulation is involved in thymic γδ T cell selection and development. Here we combine two genetic models to address this question. MiR-181a/b-1–/–mice, which show impaired agonistic T cell selection of invariant αβ NKT cells, were crossed to Tcrd-H2BeGFP reporter mice to monitor selection, intra-thymic expansion and differentiation of γδ T cells. We found that miR-181a/b-1-deficiency had no effect on numbers of thymic γδ T cell or on their differentiation towards an IL-17- or IFN-γ-producing effector phenotype. Also, the composition of peripheral lymph node γδ T cells was not affected by miR-181a/b-1-deficiency. Dendritic epidermal γδ T cells were normally present in knock-out animals. However, we observed elevated frequencies and numbers of γδ NKT cells in the liver, possibly because γδ NKT cells can expand and replace missing αβ NKT cells in peripheral niches. In summary, we investigated the role of miR-181a/b-1 for selection, intrathymic development and homeostasis of γδ T cells. We conclude that miR-181a/b-1-dependent modulation of T cell selection is not critically required for innate development of γδ NKT cells or of any other γδ T cell subtypes.

Successful β-selection depends on TCF-1 (HEM4P.228)

Abstract The transcription factor TCF-1 is expressed very early during thymic development and is important for early T cell specification. TCF-1 expression further increases after b-selection and is maintained at high levels in differentiated T cells, but its function at these later stages has not been examined. We used mice with conditional alleles of TCF-1 (TCF-1f/f) to delete TCF-1 at two time points of T cell development. Whereas deletion of TCF-1 in double-positive thymocytes (CD4-cre TCF-1f/f) had little impact on later T cell populations, the effect of the deletion at double-negative 3 (DN3) stage (CD2-cre TCF-1f/f) was dramatic. Thymic cellularity of CD2-cre TCF-1f/f mice was decreased more than 10-fold compared to littermates control, and competitive BM chimeras clearly revealed a sharp defect at the b-selection checkpoint in these mice. Analysis of TCF-1-deleted DN3 thymocytes did not reveal any defects in T cell gene expression and pre-TCR expression and signaling. However, post b-selection DN3 and DN4 thymocytes failed to display the increase in cell size and proliferation characteristic of successful b-selection. Because these two phenomena have been previously attributed to c-Myc, we examined its expression and found that c-Myc protein is reduced in TCF-1-deleted post b-selection DN3. We are currently examining the mechanism by which TCF-1 controls c-Myc. Our work to date implicates TCF-1 downstream of the pre-TCR during the development of αβ T cells.

Regulation of T-cell Responses and Disease by Tec Kinase Itk

Itk is a member of the Tec family tyrosine kinases involved in T-cell receptor signaling. The authors review the background and most recent findings of the role of Itk T-cell activation and development of αβ T cells. They also discuss the role of Itk in development of nonconventional T cells, including CD8+ innate memory phenotype T cells, different γδ T-cell populations, and invariant NKT cells. They close by reviewing the regulation of T helper differentiation and cytokine secretion, the immune response to infectious disease, and diseases such as allergic asthma and atopic dermatitis by Itk.

Presenilins regulate αβ T cell development by modulating TCR signaling

TCRαβ signaling is crucial for the maturation of CD4 and CD8 T cells, but the role of the Notch signaling pathway in this process is poorly understood. Genes encoding Presenilin (PS) 1/2 were deleted to prevent activation of the multiple Notch receptors expressed by developing thymocytes. PS1/2 knockout thymocyte precursors inefficiently generate CD4 T cells, a phenotype that is most pronounced when thymocytes bear a single major histocompatibility complex (MHC) class II–restricted T cell receptor (TCR). Diminished T cell production correlated with evidence of impaired TCR signaling, and could be rescued by manipulations that enhance MHC recognition. Although Notch appears to directly regulate binary fate decisions in many systems, these findings suggest a model in which PS-dependent Notch signaling influences positive selection and the development of αβ T cells by modifying TCR signal transduction.

Development of alphabeta T cells in the human thymus.

The thymus is the main producer of alphabeta T cells and is, therefore, crucial for a normal immune system. The intrathymic developmental pathway of human alphabeta T cells has now been delineated. The production of new T cells by the thymus decreases with age, and the thymus was thought to be redundant in adults once the peripheral T-cell pool has been formed early in life. However, recent work has shown that the thymus can function even at an advanced age. Research into the production of T cells in clinical settings that are associated with loss of T cells in the periphery has sparked renewed interest in the function of the human thymus.

The impact of pre-T-cell receptor signals on gene expression in developing T cells.

The pre-T-cell receptor (pre-TCR), which is composedof the pre-TCR-α (pTα) and TCR-β chains, is the first receptor in the development of αβ T cells that associateswith signal-transducing CD3 molecules and mediates themost effective entry into the αβ lineage. The pre-TCR,which signals via a signaling cascade similar to that of theαβ TCR, is also absolutely essential for TCRβ allelic exclusion, even though signals that determine entry into theCD4+8+ compartment of thymocytes and that mediate allelic exclusion bifurcate below the adapter protein SLP76. The pre-TCR takes away from the γδ-lineage cellswith productive TCRβ rearrangements and may thus instruct entry into the αβ lineage. It is mostly, if not exclusively, expressed on the surface of developing thymocytes as a heterodimer, utilizing the long pTα form withone extracellular immunoglobulin (Ig)-like domain.Some experiments suggest that the pre-TCR spontaneously localizes together with glycolipid-enrichedmembrane domains and may signal in a cell-autonomousfashion without binding to a ligand. Thus, the pre-TCRαprotein may not represent a mere TCRα surrogate chain,but a protein that in association with the TCRβ chain actsas a cell-autonomous developmental switch...

CD16 Cross-Linking Blocks Rearrangement of the TCRβ Locus and Development of αβ T Cells and Induces Development of NK Cells from Thymic Progenitors

AbstractMouse thymocytes normally develop into T lymphocytes, but the embryonic thymus also contains precursor cells capable of developing into NK cells. Here, we describe conditions that induce pro-T cells to develop into NK cells. CD16 is expressed on thymic pro-T cells. We observed that CD16 cross-linking during culture of embryonic thymic organs suppressed rearrangement of the TCRβ locus (but did not inhibit TCRγ locus rearrangement). Rearrangement of the TCRβ locus is normally required for development to the CD4+CD8+, and this development was also suppressed by CD16 cross-linking. The ability of CD16 cross-linking to block αβT cell development was not attributable to toxic effects, but rather was accompanied by promotion of development into NK cells, identified based on molecular and functional criteria. These results suggest that common lymphoid precursors can respond to environmental signals to commit to the αβT vs NK developmental pathways.

The αβ versus γδ T-cell lineage choice

During thymic development, immature T cells rearrange and express the genes encoding the T-cell antigen receptor and mature as either αβ or γδ lineage T cells. In the past year, advances have been made in understanding the role of individual components of the T-cell antigen receptor complex in the development of αβ and γδ lineage T cells. In addition, the transmembrane receptor Notch has recently been implicated as a new player in αβ versus γδ lineage determination.

Correction: Crucial role of the pre-T-cell receptor α gene in development of αβ but not γ§ T cells

Correction: Crucial role of the pre-T-cell receptor α gene in development of αβ but not γ§ T cells

Development of αβ T cells

Developing T cells in the thymus are subject to a screening process, through interactions with thymic stromal cells, from which T cells with appropriate T-cell receptors are selected. The recent generation of T-cell receptor transgenic mice and mice homozygous for disrupted T-cell receptor genes have now supplied tools that improve the prospect for a better understanding of the molecular mechanisms of this thymic selection process. In addition these model systems appear to indicate a role for a, not yet fully characterized, pre-T cell receptor complex in survival and further differentiation of pre-T cells.