Thymic-shared antigen-1 (TSA-1). A lymphostromal cell membrane Ly-6 superfamily molecule with a putative role in cellular adhesion (original) (raw)
Related papers
1999
Thymic shared Ag-2 (TSA-2) is a 28-kDa, glycophosphatidylinitosol-linked cell surface molecule expressed on various T cell and thymic stromal cell subsets. It is expressed on most CD3-CD4-CD8-, CD4+CD8+, and CD3highCD4-CD8+ thymocytes but is down-regulated on approximately 40% of CD3highCD4+CD8- thymocytes. Expression on peripheral TCR-alphabeta+ T cells is similar to that of CD3+ thymocytes, although a transient down-regulation occurs with cell activation. Consistent with the recent hypothesis that emigration from the thymus is an active process, recent thymic emigrants are primarily TSA-2-/low. TSA-2 expression reveals heterogeneity among subpopulations of CD3highCD4+CD8- thymocytes and TCR-gamma delta+ T cell previously regarded as homogenous. The functional importance of TSA-2 was illustrated by the severe block in T cell differentiation caused by adding purified anti-TSA-2 mAb to reconstituted fetal thymic organ culture. While each CD25/CD44-defined triple-negative subset was p...
The Journal of Immunology, 1999
Thymic shared Ag-2 (TSA-2) is a 28-kDa, glycophosphatidylinitosol-linked cell surface molecule expressed on various T cell and thymic stromal cell subsets. It is expressed on most CD3 ؊ CD4 ؊ CD8 ؊ , CD4 ؉ CD8 ؉ , and CD3 high CD4 ؊ CD8 ؉ thymocytes but is down-regulated on ϳ40% of CD3 high CD4 ؉ CD8 ؊ thymocytes. Expression on peripheral TCR-␣ ؉ T cells is similar to that of CD3 ؉ thymocytes, although a transient down-regulation occurs with cell activation. Consistent with the recent hypothesis that emigration from the thymus is an active process, recent thymic emigrants are primarily TSA-2 ؊/low. TSA-2 expression reveals heterogeneity among subpopulations of CD3 high CD4 ؉ CD8 ؊ thymocytes and TCR-␥␦ ؉ T cell previously regarded as homogenous. The functional importance of TSA-2 was illustrated by the severe block in T cell differentiation caused by adding purified anti-TSA-2 mAb to reconstituted fetal thymic organ culture. While each CD25/CD44-defined triple-negative subset was present, differentiation beyond the TN stage was essentially absent, and cell numbers of all subsets were significantly below those of control cultures. Cross-linking TSA-2 on thymocytes caused a significant Ca 2؉ influx but no increase in apoptosis, unless anti-TSA-2 was used in conjunction with suboptimal anti-CD3 mAb. Similar treatment of mature TSA-2 ؉ T cells had no effect on cell survival or proliferation. This study reveals TSA-2 to be a functionally important molecule in T cell development and a novel indicator of heterogeneity among a variety of developing and mature T cell populations.
T‐cell selection in the thymus: a spatial and temporal perspective
Immunological Reviews, 2016
SummaryThe ability of T cells to respond to a wide array of foreign antigens while avoiding reactivity to self is largely determined by cellular selection of developing T cells in the thymus. While a great deal is known about the cell types and molecules involved in T‐cell selection in the thymus, our understanding of the spatial and temporal aspects of this process remain relatively poorly understood. Thymocytes are highly motile within the thymus and travel between specialized microenvironments at different phases of their development while interacting with distinct sets of self‐peptides and peptide presenting cells. A knowledge of when, where, and how thymocytes encounter self‐peptide MHC ligands at different stages of thymic development is key to understanding T‐cell selection. In the past several years, our laboratory has investigated this topic using two‐photon time‐lapse microscopy to directly visualize thymocyte migration and signaling events, together with a living thymic s...
Immunity, 1999
tive transfer experiments with CD8 ϩ cells from MHC class I (H2-D b )-reactive HY TCR transgenic mice showed that CD8 ϩ cells survived well in H2-D bϩ hosts but disappeared rapidly in H2-D bϪ mice. The above findings imply that survival of mature naive CD4 ϩ and CD8 ϩ T cells requires continuous, albeit covert, signaling through the TCR. In support of this idea, Summary T cells deficient in a Kruppel-like zinc finger transcription factor designated lung Kruppel-like factor (LKLF) were Positive selection to self-MHC/peptide complexes has found to have a very short life span (Kuo et al., 1997). long been viewed as a device for skewing the T cell Interestingly, LKLF Ϫ embryonic stem cells led to normal repertoire toward recognition of foreign peptides pre-T cell development in the thymus but to the appearance sented by self-MHC molecules. Here, we provide eviof only a few mature T cells in the periphery, because dence for an alternative possibility, namely, that the the T cells underwent spontaneous activation and died self-peptides controlling positive selection in the thyrapidly from Fas-mediated apoptosis. LKLF thus apmus serve to maintain the longevity of mature T cells pears to be involved in translating the low-level TCR in the periphery. Surprisingly, when total T cell numsignaling received from contact with self-MHC molebers are reduced, these self-ligands become overtly cules into signals for mature T cells to persist in the stimulatory and cause naive T cells to proliferate and quiescent state. undergo homeostatic expansion.
Rare, Structurally Homologous Self-Peptides Promote Thymocyte Positive Selection
Immunity, 2002
Division of Immunology ligands involved in positive selection would be low-affinity nonstimulatory ligands (Lo and Sprent, 1986). Several reports suggested that subthreshold densities of a stimulatory peptide/MHC ligand were capable of promoting ture, were functionally altered (Girao et al., 1997; Kraj et al., 2001a; Sebzda et al., 1996). Peptides that antagonize Center for Immunology University of Minnesota mature T cell responses were also able to induce positive selection in fetal thymus organ cultures (FTOC) MMC 334 420 Delaware Street SE (Hogquist et al., 1994; Jameson et al., 1994; Smyth et al., 1998) and in vivo (Stefanski et al., 2001). However, Minneapolis, Minnesota 55455 5 Biomedical Mass Spectrometry and Functional others have shown that the presence of an antagonist peptide failed to promote (Basu et al., 1998; Williams et Proteomics Facility and Department of Biochemistry and Molecular Biology al., 1996) or impaired positive selection (Kraj et al., 2001a; Spain et al., 1994). Finally, three studies showed Mayo Clinic Rochester, Minnesota 55905 that apparently unrelated peptide/MHC complexes were able to induce positive selection (Ignatowicz et al., 1997; Nakano et al., 1997; Pawlowski et al., 1996). However, all of these studies suffer from the same drawback: Summary while they describe ligands that can promote positive selection in experimental situations, they may not accu-Although it is clear that positive selection of T cells rately reflect the properties of the natural self-peptide/ involves recognition of specific self-peptide/MHC com-MHC ligands that drive positive selection in vivo. plexes, the nature of these self-ligands and their rela-We identified a naturally occurring self-peptide (pretionship to the cognate antigen are controversial. Here viously called CP␣1 but hereafter referred to as we used two complementary strategies to identify nat-Cappa1 92-99 ) that induced positive selection of the OT-I urally occurring self-peptides able to induce positive TCR (Hogquist et al.,
Molecular Immunology, 2008
The stem cells which seed the thymus bear neither receptors for antigen nor the coreceptors which are characteristic of mature T cells, CD4 or CD8. After entering the thymus, cells destined to bear T cell receptors (TCRs) made up of ␣ and  chains, construct the genes for these chains by rearranging one of many V␣s to lie next to one of many J␣s, and one of many Vs to lie next to one or more version of D and one of a number of Js . Since all these elements are encoded by the germ line, one might imagine that TCR+ thymocytes might have a very large, but genetically fixed, set of specificities for antigen. However, nucleotides can be removed or introduced at the junctions between these elements, and thus these joining points (N regions) are quite random, and not genetically controlled . N regions code for part of the CDR3 loops of TCR␣ and  polypeptides and the CDR3 regions are a major component of the area of TCRs which contact their ligands . Consequently the germ line specificities of TCRs are modified by their nongerm line N regions and thymocytes bear TCRs which manifest their germline encoded specificities to varying degrees.
International Immunology, 2000
Experiments with synthetic antigen peptides have suggested that a critical parameter that determines the developmental fate of an immature thymocyte is the affinity of interaction between TCR and self-peptide/MHC expressed on thymic stromal cells. To test the physiological relevance of this model for thymocyte development, we determined the affinity of the anti-HY TCR (B6.2.16) expressed on CD8 ⍣ cells for thymic self-peptide/H-2D b tetramers, then examined the ability of these self-peptides to determine the outcome of B6.2.16 CD8 cell selection in the thymus. The B6.2.16 TCR bound the male HY self-antigen with high affinity. Thymic self-peptides, which are highly abundant on the surface of thymic epithelial cells, bound the B6.2.16 TCR with low affinity. The ability of self-peptides to trigger positive or negative selection of B6.2.16 CD8 cells in cultured fetal thymi was determined by the relative affinity of self-peptide/H-2D b for the B6.2.16 TCR. Highaffinity binding of the HY self-peptide resulted in B6.2.16 TCR complex ζ chain phosphorylation and the negative selection of B6.2.16 CD8 cells. Low-affinity binding of thymic self-peptides to B6.2.16 TCR resulted in the positive selection of B6.2.16 CD8 cells. Differences between the binding affinities of self-peptides to B6.2.16 TCR accounted for the self-peptide specificity of B6.2.16 CD8 cell positive selection. We conclude that the relative affinity of TCR for thymic selfpeptide/class I MHC is a critical parameter in determining fate of CD8 ⍣ cells during thymic selection.