T-cell receptor gamma delta and gamma transgenic mice suggest a role of a gamma gene silencer in the generation of alpha beta T cells.

Structural diversity of lymphocyte antigen receptors (the immunoglobulin [Ig] of B cells and the alpha/beta or gamma/delta T cell receptor [TCR] of T cells) is generated through somatic rearrangements of V, D, and J gene segments. Classically, these recombination events involve gene segments from the same Ig or TCR locus. However, occurrence of "trans" rearrangements between distinct loci has also been described, although in no instances was the surface expression of the corresponding protein under normal physiological conditions demonstrated. Here we show that hybrid TCR genes generated by trans rearrangement between V gamma and (D) J beta elements are translated into functional antigen receptor chains, paired with TCR alpha chains. Like classical alpha/beta T cells, cells expressing these hybrid TCR chains express either CD4 or CD8 coreceptors and are frequently alloreactive. These results have several implications in terms of T cell repertoire selection and relationships between TCR structure and specificity. First, they suggest that TCR alloreactivity is determined by the repertoire selection processes operating during lymphocyte development rather than by structural features specific to V alpha V beta regions. Second, they suggest the existence of close structural relationships between gamma/delta and alpha/beta TCR and more particularly, between V gamma and V beta regions. Finally, since a significant fraction of PBL (at least 1/10(4)) expressed hybrid TCR chains on their surface, these observations indicate that trans rearrangements significantly contribute to the combinatorial diversification of the peripheral immune repertoire.

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Stringent V beta requirement for the development of NK1.1+ T cell receptor-alpha/beta+ cells in mouse liver.

Journal of Experimental Medicine ◽

10.1084/jem.183.3.1277 ◽

1996 ◽

Vol 183 (3) ◽

pp. 1277-1282 ◽

Cited By ~ 53

Author(s):

T Ohteki ◽

H R MacDonald

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Beta Cells ◽

T Cell Receptor ◽

Cell Receptor ◽

Allelic Exclusion ◽

Stringent Requirement ◽

Major Subset ◽

Alpha Beta

The liver of C57BL/6 mice contains a major subset of CD4+8- and CD4-8- T cell receptor (TCR)-alpha/beta+ cells expressing the polymorphic natural killer NK1.1 surface marker. Liver NK1.1+TCR-alpha/beta+ (NK1+ T) cells require interaction with beta2-microglobulin-associated, major histocompatibility complex I-like molecules on hematopoietic cells for their development and have a TCR repertoire that is highly skewed to Vbeta8.2, Vbeta7, and Vbeta2. We show here that congenic C57BL/6.Vbeta(a) mice, which lack Vbeta8- expressing T cells owing to a genomic deletion at the Vbeta locus, maintain normal levels of liver NK1+ T cells owing to a dramatic increase in the proportion of cells expressing Vbeta7 and Vbeta2 (but not other Vbetas). Moreover, in C57BL/6 congenic TCR-V Vbeta3 and -Vbeta8.1 transgenic mice (which in theory should not express other Vbeta, owing to allelic exclusion at the TCR-beta locus), endogenous TCR-Vbeta8.2, Vbeta7, and Vbeta2 (but not other Vbetas) are frequently expressed on liver NK1+T cells but absent on lymph node T cells. Finally, when endogenous V beta expression is prevented in TCR-Vbeta3 and Vbeta8.1 transgenic mice (by introduction of a null allele at the C beta locus), the development of liver NK1+T cells is totally abrogated. Collectively, our data indicate that liver NK1+T cells have a stringent requirement for expression of TCR-Vbeta8.2, Vbeta7, or Vbeta2 for their development.

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Faculty Opinions recommendation of Unique role of CD4+CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1019222.241532 ◽

2004 ◽

Author(s):

Richard Williams

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Transgenic Mice ◽

T Cell Receptor ◽

Autoimmune Diabetes ◽

Cell Receptor ◽

Unique Role

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Skewed T-cell receptor usage and junctional heterogeneity among isletitis alpha beta and gamma delta T-cells in human IDDM [corrected]

Diabetes ◽

10.2337/diabetes.43.4.599 ◽

1994 ◽

Vol 43 (4) ◽

pp. 599-606 ◽

Cited By ~ 13

Author(s):

P. Santamaria ◽

C. Lewis ◽

J. Jessurun ◽

D. E. Sutherland ◽

J. J. Barbosa

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Gamma Delta T Cells ◽

Gamma Delta ◽

Receptor Usage ◽

Alpha Beta

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Unique role of CD4+CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0404870101 ◽

2004 ◽

Vol 101 (Supplement 2) ◽

pp. 14580-14585 ◽

Cited By ~ 69

Author(s):

S. You ◽

G. Slehoffer ◽

S. Barriot ◽

J.-F. Bach ◽

L. Chatenoud

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Transgenic Mice ◽

T Cell Receptor ◽

Autoimmune Diabetes ◽

Cell Receptor ◽

Unique Role

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The life span of naive alpha/beta T cells in secondary lymphoid organs.

Journal of Experimental Medicine ◽

10.1084/jem.177.4.891 ◽

1993 ◽

Vol 177 (4) ◽

pp. 891-896 ◽

Cited By ~ 97

Author(s):

H von Boehmer ◽

K Hafen

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Life Span ◽

T Cell Receptor ◽

Cell Receptor ◽

Lymphoid Organs ◽

Alpha Beta ◽

Secondary Lymphoid Organs ◽

Deficient Mice

We have determined the life span of naive CD4-8+ T cells in T cell receptor transgenic mice. We find that such cells do not divide in secondary lymphoid organs in both normal euthymic mice and T cell-deficient mice. By both continuous labeling and by chasing pulse-labeled cells, we find that the minimum life span of the naive T cells is in the order of 8 wk.

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Resistance to cutaneous graft-vs.-host disease is not induced in T cell receptor delta gene-mutant mice.

Journal of Experimental Medicine ◽

10.1084/jem.183.4.1483 ◽

1996 ◽

Vol 183 (4) ◽

pp. 1483-1489 ◽

Cited By ~ 45

Author(s):

T Shiohara ◽

N Moriya ◽

J Hayakawa ◽

S Itohara ◽

H Ishikawa

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Gamma Delta ◽

Autoreactive T Cells ◽

Host Disease ◽

Large Numbers ◽

Graft Vs Host Disease ◽

Alpha Beta

The function of murine dendritic epidermal cells (dEC) remains largely speculative, probably because of the lack of a suitable in vivo model, although previous studies suggest that gamma/delta+ dEC may have originally evolved to serve as a self-protection mechanism(s). Our previous study demonstrated that the epidermis of mice that had spontaneously recovered from cutaneous graft-vs-host disease (GVHD) induced by local injection of CD4+ autoreactive T cells contained unexpectedly large numbers of dEC and became resistant to subsequent attempts to induce GVHD in a site-restricted manner, suggesting that the resistance is mediated by dEC. However, because alpha/beta+ dEC as well as gamma/delta+ dEC were greatly increased in number in the epidermis, it was unclear whether gamma/delta+ dEC are indeed responsible for this protection. The availability of this murine model and mice selectively lacking gamma/delta T cells as a result of disruption of the T cell receptor C delta gene segment allowed us to investigate the role of gamma/delta+ dEC. In the epidermis of gamma/delta T cell-deficient mice (delta-/-), a congenital lack of gamma/delta+ dEC was substituted for by alpha/beta+ dEC of either a CD4-8+ or a CD4-8- phenotype. After intradermal injection of the autoreactive T cells, delta-/- mice developed significantly enhanced delayed-type hypersensitivity responses and cutaneous GVHD, which persisted longer than in heterozygous littermate controls (delta+/-). Surprisingly, resistance to the cutaneous GVHD was not induced in the epidermis of delta-/- mice after spontaneous recovery from the GVHD, whereas the "susceptible" epidermis of delta-/+ mice contained large numbers of alpha/beta dEC comparable to those in "resistant" epidermis of delta+/- mice. Injection of day 16 fetal thymocytes from wild-type mice into delta-/- mice resulted in the appearance of donor-type gamma/delta+ dEC in the epidermis, and reconstitution with gamma/delta+ dEC restored the protective immune response of the epidermis against the GVHD to nearly normal levels. These results indicate that gamma/delta+ dEC are responsible for the site-restricted protection against cutaneous GVHD.

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Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22052713 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2713

Author(s):

Sun-Hye Shin ◽

Kyung-Ah Cho ◽

Hee-Soo Yoon ◽

So-Yeon Kim ◽

Hee-Yeon Kim ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Acyl Chain ◽

Signal Strength ◽

Cell Receptor ◽

Ceramide Synthase ◽

Asthmatic Patients

(1) Background: six mammalian ceramide synthases (CerS1–6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22–C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

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CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer

Journal of Experimental Medicine ◽

10.1084/jem.20011845 ◽

2002 ◽

Vol 196 (4) ◽

pp. 481-492 ◽

Cited By ~ 62

Author(s):

Kristin V. Tarbell ◽

Mark Lee ◽

Erik Ranheim ◽

Cheng Chi Chao ◽

Maija Sanna ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

T Cell Receptor ◽

Glutamic Acid Decarboxylase ◽

Cd4 T Cells ◽

Cell Receptor ◽

Acid Decarboxylase ◽

Gad 65

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

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Depletion of alpha/beta T cells by a monoclonal antibody against the alpha/beta T cell receptor suppresses established adjuvant arthritis, but not established collagen-induced arthritis in rats.

Journal of Experimental Medicine ◽

10.1084/jem.175.4.907 ◽

1992 ◽

Vol 175 (4) ◽

pp. 907-915 ◽

Cited By ~ 40

Author(s):

S Yoshino ◽

L G Cleland

Keyword(s):

Monoclonal Antibody ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Adjuvant Arthritis ◽

Inflammatory Cells ◽

Cell Receptor ◽

Collagen Induced Arthritis ◽

Alpha Beta ◽

Synovial Tissues

The effects of treatment with a monoclonal antibody (R73 mAb) against T cell receptor alpha/beta (TCR-alpha/beta) on both established adjuvant arthritis (EAA) and established collagen-induced arthritis (ECIA) in rats have been investigated. Rats were treated with R73 mAb when arthritis reached a peak. Treatment with the anti-TCR-alpha/beta mAb markedly suppressed EAA, whereas ECIA was not affected by the mAb treatment. Histologically, R73 mAb-treated rats with EAA showed mild hyperplasia of synovial tissues, sparse infiltration of inflammatory cells, and minimal erosion of cartilage, whereas arthritic rats treated with PBS and an irrelevant control mAb against Giardia had marked hyperplasia of synovium with pannus, massive inflammatory cell infiltrate, and severe destruction of cartilage and subchondral bone. R73 mAb-treated rats with ECIA exhibited pronounced formation of pannus containing many inflammatory cells and marked cartilage and subchondral damage similar to those in arthritic rats that received the control treatments. Treatment with R73 mAb depleted markedly alpha/beta+ T cells in both peripheral blood and synovial tissues of rats with EAA and ECIA. R73 mAb treatment was associated with marked reduction in arthritogen-specific delayed-type hypersensitivity responses in both EAA and ECIA. The titers of antibodies against type II collagen produced in rats with ECIA were not affected by the mAb. Thus, alpha/beta+ T cells appear to have a central role in EAA, but not in chronic ECIA.

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