scholarly journals Positive and negative selection of T cell receptor V beta domains controlled by distinct cell populations in the thymus.

1989 ◽  
Vol 170 (6) ◽  
pp. 2165-2170 ◽  
Author(s):  
D E Speiser ◽  
R K Lees ◽  
H Hengartner ◽  
R M Zinkernagel ◽  
H R MacDonald
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Negative Selection ◽  
T Cell Development ◽  
Cell Receptor ◽  
Distinct Cell ◽  
Tcr Repertoire ◽  
Bone Marrow Chimeras ◽  
Selection Of

The role of thymic MHC class II-bearing cells in the selection of the TCR repertoire has been investigated in allogeneic radiation bone marrow chimeras. Positive selection of mature CD4+ T lymphocytes expressing the V beta 6+ TCR domain was found to depend upon radioresistant (presumably epithelial) I-E+ thymic cells. On the other hand, negative selection of CD4+ V beta 6+ cells (which was additionally dependent upon expression of the Mls-1a gene product) was controlled by a radiosensitive I-E+ thymic component (most likely dendritic cells). These data argue in favor of a compartmentalization of positive and negative selection events during T cell development.

scholarly journals Role of the Multiple T Cell Receptor (TCR)-ζ Chain Signaling Motifs in Selection of the T Cell Repertoire

1997 ◽  
Vol 185 (5) ◽  
pp. 893-900 ◽  
Author(s):  
Elizabeth W. Shores ◽  
Tom Tran ◽  
Alexander Grinberg ◽  
Connie L. Sommers ◽  
Howard Shen ◽  
...  
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
Selection Process ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Ligand Interaction ◽  
Competent Self ◽  
Selection Of

Immature thymocytes undergo a selection process within the thymus based on their T cell antigen receptor (TCR) specificity that results either in their maturation into functionally competent, self-MHC–restricted T cells (positive selection) or their deletion (negative selection). The outcome of thymocyte selection is thought to be controlled by signals transduced by the TCR that vary in relation to the avidity of the TCR–ligand interaction. The TCR is composed of four distinct signal transducing subunits (CD3-γ, -δ, -ε, and ζ) that contain either one (CD3-γ, -δ, -ε) or three (-ζ) signaling motifs (ITAMs) within their intracytoplasmic domains. A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection. To determine the importance of the multiple TCR-ζ chain ITAMs in thymocyte selection, transgenes encoding α/βTCRs with known specificity were bred into mice in which ζ chains lacking one or more ITAMs had been genetically substituted for endogenous ζ. A direct relationship was observed between the number of ζ chain ITAMs within the TCR complex and the efficiency of both positive and negative selection. These results reveal a role for multiple TCR ITAMs in thymocyte selection and identify a function for TCR signal amplification in formation of the T cell repertoire.

scholarly journals Notch-Induced Endoplasmic Reticulum-Associated Degradation Governs Thymocyte β-Selection

2021 ◽  
Author(s):  
Xi Chen ◽  
Xia Liu ◽  
Jingjing Yu ◽  
Longyong Xu ◽  
Katharine Umphred-Wilson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Translational Activity ◽  
Notch Intracellular Domain ◽  
Tcr Repertoire ◽  
Thymocyte Apoptosis ◽  
Selection Of

Signals from the pre-T cell receptor and Notch coordinately instruct β-selection of CD4−CD8− double negative (DN) thymocytes to generate αβ T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by b-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during β-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired αβ T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from Sel1l-deficient thymocytes. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.

The role of the T cell receptor in positive and negative selection of developing T cells

Science ◽  
1990 ◽  
Vol 248 (4961) ◽  
pp. 1335-1341 ◽  
Author(s):  
M Blackman ◽  
J Kappler ◽  
P Marrack
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
Selection Of

scholarly journals A Role for Fas in Negative Selection of Thymocytes In Vivo

1998 ◽  
Vol 187 (9) ◽  
pp. 1427-1438 ◽  
Author(s):  
Hidehiro Kishimoto ◽  
Charles D. Surh ◽  
Jonathan Sprent
Keyword(s):  
Negative Selection ◽  
Cell Receptor ◽  
Staphylococcal Enterotoxin B ◽  
Thymic Medulla ◽  
Enterotoxin B ◽  
High Doses ◽  
Specific Peptide ◽  
Selection Of

To seek information on the role of Fas in negative selection, we examined subsets of thymocytes from normal neonatal mice versus Fas-deficient lpr/lpr mice injected with graded doses of antigen. In normal mice, injection of 1–100 μg of staphylococcal enterotoxin B (SEB) induced clonal elimination of SEB-reactive Vβ8+ cells at the level of the semi-mature population of HSAhi CD4+ 8− cells found in the thymic medulla; deletion of CD4+ 8+ cells was minimal. SEB injection also caused marked elimination of Vβ8+ HSAhi CD4+ 8− thymocytes in lpr/lpr mice. Paradoxically, however, elimination of these cells in lpr/lpr mice was induced by low-to-moderate doses of SEB (≤1 μg) but not by high doses (100 μg). Similar findings applied when T cell receptor transgenic mice were injected with specific peptide. These findings suggest that clonal elimination of semi-mature medullary T cells is Fas independent at low doses of antigen but Fas dependent at high doses. Previous reports documenting that negative selection is not obviously impaired in lpr/lpr mice could thus reflect that the antigens studied were expressed at only a low level.

scholarly journals Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity

2017 ◽  
Vol 214 (11) ◽  
pp. 3417-3433 ◽  
Author(s):  
Xiaojing Chen ◽  
Lucia Poncette ◽  
Thomas Blankenstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Mhc Molecules ◽  
Mhc Ii ◽  
Cdr3 Length ◽  
Tcr Repertoire ◽  
Cell Diversity ◽  
Antigen Presenting

For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.

Antigen-induced apoptosis in developing t cells: a mechanism for negative selection of the t cell receptor repertoire*

1989 ◽  
Vol 19 (11) ◽  
pp. 2175-2177 ◽  
Author(s):  
Eric J. Jenkinson ◽  
Rosetta Kingston ◽  
Christopher A. Smith ◽  
Gwynn T. Williams ◽  
John J. T. Owen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
Receptor Repertoire ◽  
Induced Apoptosis ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire ◽  
Selection Of

Gimap4 accelerates T-cell death

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 591-599 ◽  
Author(s):  
Silke Schnell ◽  
Corinne Démollière ◽  
Paul van den Berk ◽  
Heinz Jacobs
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Critical Role ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Physiology ◽  
Double Positive ◽  
Pkc Activation ◽  
Null Mutant Mouse

Gimap4, a member of the newly identified GTPase of the immunity-associated protein family (Gimap), is strongly induced by the pre–T-cell receptor in precursor T lymphocytes, transiently shut off in double-positive thymocytes, and reappears after TCR-mediated positive selection. Here, we show that Gimap4 remains expressed constitutively in the cytosol of mature T cells. A C-terminal IQ domain binds calmodulin in the absence of calcium, and conserved PKC phosphorylation motifs are targets of concanavalin A (ConA)– or PMA/ionomycin-induced PKC activation. To address the role of Gimap4 in T-cell physiology, we completed the genomic organization of the gimap4 locus and generated a Gimap4-null mutant mouse. Studies in these mice revealed no critical role of Gimap4 in T-cell development but in the regulation of apoptosis. We have found that Gimap4 accelerates the execution of programmed cell death induced by intrinsic stimuli downstream of caspase-3 activation and phosphatidylserine exposure. Apoptosis directly correlates with the phosphorylation status of Gimap4.

Sign in / Sign up

Export Citation Format

Share Document