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1.
Nature ; 414(6865): 792-8, 2001 Dec 13.
Article in English | MEDLINE | ID: mdl-11742411

ABSTRACT

The hallmark of type 1 diabetes is specific destruction of pancreatic islet beta-cells. Apoptosis of beta-cells may be crucial at several points during disease progression, initiating leukocyte invasion of the islets and terminating the production of insulin in islet cells. beta-Cell apoptosis may also be involved in the occasional evolution of type 2 into type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 2/pathology , Islets of Langerhans/pathology , Animals , Autoantigens/immunology , Autoimmunity , Cell Death , Diabetes Mellitus, Type 1/etiology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/immunology , Disease Progression , Humans , Inflammation Mediators/metabolism , Islets of Langerhans/immunology , Mice , T-Lymphocytes/immunology
2.
Am J Pathol ; 159(5): 1689-99, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11696430

ABSTRACT

There is considerable evidence that osteoclasts are involved in the pathogenesis of focal bone erosion in rheumatoid arthritis. Tumor necrosis factor-related activation-induced cytokine, also known as receptor activator of nuclear factor-kappaB ligand (TRANCE/RANKL) is an essential factor for osteoclast differentiation. In addition to its role in osteoclast differentiation and activation, TRANCE/RANKL also functions to augment T-cell dendritic cell cooperative interactions. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, we generated inflammatory arthritis in the TRANCE/RANKL knockout mouse using a serum transfer model that bypasses the requirement for T-cell activation. These animals exhibit an osteopetrotic phenotype characterized by the absence of osteoclasts. Inflammation, measured by clinical signs of arthritis and histopathological scoring, was comparable in wild-type and TRANCE/RANKL knockout mice. Microcomputed tomography and histopathological analysis demonstrated that the degree of bone erosion in TRANCE/RANKL knockout mice was dramatically reduced compared to that seen in control littermate mice. In contrast, cartilage erosion was present in both control littermate and TRANCE/RANKL knockout mice. These results confirm the central role of osteoclasts in the pathogenesis of bone erosion in arthritis and demonstrate distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis.


Subject(s)
Arthritis/diagnosis , Arthritis/metabolism , Bone and Bones/diagnostic imaging , Bone and Bones/pathology , Membrane Glycoproteins/deficiency , Animals , Arthritis/blood , Arthritis/etiology , Blood Transfusion , Carrier Proteins/genetics , Carrier Proteins/physiology , Cartilage, Articular/diagnostic imaging , Cartilage, Articular/pathology , Disease Models, Animal , Membrane Glycoproteins/genetics , Membrane Glycoproteins/physiology , Mice , Mice, Knockout/genetics , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Tomography, X-Ray Computed
3.
Nat Immunol ; 2(12): 1117-25, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11713466

ABSTRACT

The progression of autoimmune diabetes is regulated. We examined here the cellular controls exerted on disease that developed in the BDC2.5 T cell receptor-transgenic model. We found that all BDC2.5 mice with a monoclonal, beta cell-reactive, T cell repertoire developed diabetes before 4 weeks of age; transfer of splenocytes from young standard NOD (nonobese diabetic) mice into perinatal monoclonal BDC2.5 animals protected them from diabetes. The protective activity was generated by CD4+ alphabeta T cells, which operated for a short time at disease initiation, could be partitioned according to DX5 cell surface marker expression and split into two components. Protection did not involve clonal deletion or anergy of the autoreactive BDC2.5 cells, permitting their full activation and attack of pancreatic islets; rather, it tempered the aggressiveness of the insulitic lesion and the extent of beta cell destruction.


Subject(s)
Autoimmunity , CD4-Positive T-Lymphocytes/immunology , Diabetes Mellitus, Type 1/immunology , Adoptive Transfer , Animals , Antigens, Surface/analysis , CD4-Positive T-Lymphocytes/transplantation , Cytokines/genetics , Cytokines/physiology , Diabetes Mellitus, Type 1/pathology , Disease Progression , Genes, T-Cell Receptor , Immunophenotyping , Kinetics , Lymphocyte Depletion , Mice , Mice, Inbred NOD , Mice, Knockout , Mice, Transgenic , Pancreas/pathology , Self Tolerance , T-Lymphocyte Subsets/classification
4.
Eur J Immunol ; 31(9): 2583-92, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11536156

ABSTRACT

As a new slant on T lymphocyte repertoire selection, we have examined batteries of TCR sequences in thymi from transgenic mice engineered to exhibit limited, focussed TCR diversity. We have tracked the fate of differentiating thymocytes expressing a set of particular TCR through the positive selection process. Subtly different TCR sequences can promote different maturation pathways and commitment choices. Two distinct routes are followed by CD8-lineage cells interacting with MHC class I molecules, via TCR(hi) CD4(+)CD8(+) or CD4(+)CD8(int) intermediates, while CD4-lineage cells mature exclusively via a CD4(+)CD8(int) stage. The CD8-lineage routes are partially exclusive, indicating that the latter cell type is not always preceded by the former. The distribution of sequences also indicates that CD4 / CD8-lineage commitment is not strictly correlated with the class of MHC molecule engaged, and that some mechanism prevents mismatched intermediates from achieving full maturity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Thymus Gland/immunology , Amino Acid Sequence , Animals , Cell Lineage , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Mice , Mice, Knockout , Mice, Transgenic , Models, Immunological , Stem Cells/immunology
5.
Nat Immunol ; 2(9): 797-801, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11526389

ABSTRACT

Autoimmune diseases remain one of the mysteries that perplex immunologists. What makes the immune system, which has evolved to protect an organism from foreign invaders, turn on the organism itself? A popular answer to this question involves the lymphoid network's primordial function: autoimmunity is a by-product of the immune response to microbial infection. For decades there have been tantalizing associations between infectious agents and autoimmunity: beta-hemolytic streptococci and rheumatic fever; B3 Coxsackieviruses and myocarditis; Trypanosoma cruzi and Chagas' disease; diverse viruses and multiple sclerosis; Borrelia burgdorfii and Lyme arthritis; and B4 Coxsackievirus, cytomegalovirus or rubella and type 1 diabetes, to name the most frequently cited examples. In addition, animal models have provided direct evidence that infection with a particular microbe can incite a particular autoimmune disease. Nonetheless, many of the associations appear less than convincing and, even for those that seem to be on solid footing, there is no real understanding of the underlying mechanism(s).


Subject(s)
Autoimmune Diseases/immunology , Autoimmunity , Capsid Proteins , Epitopes, T-Lymphocyte/immunology , Lipoproteins , Molecular Mimicry , Antigens, Surface/immunology , Autoantigens/immunology , Bacterial Outer Membrane Proteins/immunology , Bacterial Vaccines , Capsid/immunology , Eye Proteins/immunology , Humans , Keratitis, Herpetic/immunology , Lyme Disease/immunology , Lyme Disease Vaccines/immunology , Lymphocyte Function-Associated Antigen-1/immunology , Models, Immunological , Viral Proteins
6.
J Exp Med ; 194(3): 321-30, 2001 Aug 06.
Article in English | MEDLINE | ID: mdl-11489951

ABSTRACT

K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, most similar to rheumatoid arthritis, that is critically dependent on both T and B lymphocytes. Transfer of serum, or just immunoglobulins, from arthritic K/BxN animals into healthy recipients provokes arthritis efficiently, rapidly, and with high penetrance. We have explored the genetic heterogeneity in the response to serum transfer, thereby focussing on the end-stage effector phase of arthritis, leap-frogging the initiating events. Inbred mouse strains showed clear variability in their responses. A few were entirely refractory to disease induction, and those which did develop disease exhibited a range of severities. F1 analyses suggested that in most cases susceptibility was controlled in a polygenic additive fashion. One responder/nonresponder pair (C57Bl/6 x NOD) was studied in detail via a genome scan of F2 mice; supplementary information was provided by the examination of knock-out and congenic strains. Two genomic regions that are major, additive determinants of the rapidity and severity of K/BxN serum-transferred arthritis were highlighted. Concerning the first region, on proximal chromosome (chr)2, candidate assignment to the complement gene C5 was confirmed by both strain segregation analysis and functional data. Concerning the second, on distal chr1, coinciding with the Sle1 locus implicated in susceptibility to lupus-like autoimmune disease, a contribution by the fcgr2 candidate gene was excluded. Two other regions, on chr12 and chr18 may also contribute to susceptibility to serum-transferred arthritis, albeit to a more limited degree. The contributions of these loci are additive, but gene dosage effects at the C5 locus are such that it largely dominates. The clarity of these results argues that our focus on the terminal effector phase of arthritis in the K/BxN model will bear fruit.


Subject(s)
Arthritis/genetics , Animals , Arthritis/etiology , Arthritis/immunology , Base Sequence , Chromosome Mapping , DNA Primers/genetics , Disease Models, Animal , Female , Humans , Hybridization, Genetic , Male , Mice , Mice, Inbred NOD , Mice, Inbred Strains , Mice, Knockout , Mice, Transgenic , Microsatellite Repeats , Phenotype , Receptors, Antigen, T-Cell/genetics
7.
Immunity ; 15(1): 71-82, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11485739

ABSTRACT

Kinetic features of TCR:MHC/peptide interactions dictate their outcome in vitro, some important parameters of which include the number of molecules engaged and the duration of engagement. We explored the in vivo significance of these findings in transgenic mice expressing TCRs in a quantitatively and temporally controlled manner. As anticipated, reduced TCR levels resulted in attenuated reactivity, but response thresholds were substantially lower than expected-at as low as 1/20th the normal TCR numbers and with no indication of phenotypic skewing at suboptimal levels. We also studied survival of T lymphocytes stripped of their TCRs. Unlike B cells, T cells lacking antigen receptors did not die precipitously; instead, populations decayed gradually, just as previously reported in the absence of MHC molecules.


Subject(s)
Receptors, Antigen, T-Cell/physiology , T-Lymphocytes/physiology , Animals , Cytokines/biosynthesis , Histocompatibility Antigens/physiology , Mice , Mice, Transgenic , Receptors, Antigen, T-Cell/analysis , Tetracycline/pharmacology
8.
J Immunol ; 167(2): 741-8, 2001 Jul 15.
Article in English | MEDLINE | ID: mdl-11441078

ABSTRACT

The dendritic cells (DC) of mouse lymph nodes (LN) were isolated, analyzed for surface markers, and compared with those of spleen. Low to moderate staining of LN DC for CD4 and low staining for CD8 was shown to be attributable to pickup of these markers from T cells. Excluding this artifact, five LN DC subsets could be delineated. They included the three populations found in spleen (CD4(+)8(-)DEC-205(-), CD4(-)8(-)DEC-205(-), CD4(-)8(+)DEC-205(+)), although the CD4-expressing DC were of low incidence. LN DC included two additional populations, characterized by relatively low expression of CD8 but moderate or high expression of DEC-205. Both appeared among the DC migrating out of skin into LN, but only one was restricted to skin-draining LN and was identified as the mature form of epidermal Langerhans cells (LC). The putative LC-derived DC displayed the following properties: large size; high levels of class II MHC, which persisted to some extent even in CIITA null mice; expression of very high levels of DEC-205 and of CD40; expression of many myeloid surface markers; and no expression of CD4 and only low to moderate expression of CD8. The putative LC-derived DC among skin emigrants and in LN also showed strong intracellular staining of langerin.


Subject(s)
Dendritic Cells/cytology , Lectins, C-Type , Lymph Nodes/cytology , Mannose-Binding Lectins , Nuclear Proteins , Animals , Antigens, Surface/analysis , Biomarkers/analysis , CD4 Antigens/biosynthesis , CD8 Antigens/biosynthesis , Cell Movement/immunology , Cells, Cultured , Dendritic Cells/immunology , Dendritic Cells/metabolism , Female , Fluorescein-5-isothiocyanate/metabolism , Fluorescent Dyes/metabolism , Langerhans Cells/cytology , Langerhans Cells/immunology , Langerhans Cells/metabolism , Lymph Nodes/immunology , Lymph Nodes/metabolism , Mesentery/cytology , Mice , Mice, Inbred C57BL , Mice, Knockout , Organ Culture Techniques , Rhodamines/metabolism , Skin/cytology , Spleen/cytology , Staining and Labeling , Trans-Activators/physiology
9.
Int Immunol ; 13(6): 763-8, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11369703

ABSTRACT

The role of IL-4, -6 and -7 in the survival of T lymphocytes was studied in vivo. The decay of polyclonal populations of CD4(+) and CD8(+) T cells was monitored in thymectomized anti-cytokine receptor mAb-treated and/or cytokine-deficient mice. The lack of IL-4 or -6 did not have any detectable effect on T cell survival, but IL-7 played an important role in the survival of the naive T cell compartment, especially of naive CD4(+) T cells.


Subject(s)
Interleukin-4/physiology , Interleukin-6/physiology , Interleukin-7/physiology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Animals , Cell Survival/immunology , Immunophenotyping , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Receptors, Interleukin-7/deficiency , Receptors, Interleukin-7/genetics , Receptors, Interleukin-7/physiology , Signal Transduction/genetics
10.
Immunity ; 14(1): 21-32, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11163227

ABSTRACT

By combining a TCRbeta transgene with a TCRalpha minilocus comprised of a single V and two J gene segments, we engineered a mouse line exhibiting ample but focused TCR diversity, restricted to CDR3alpha. Using single-cell PCR and high-throughput sequencing, we have exploited this system to scrutinize T cell repertoire selection and evolution. Some striking observations emerged: (1) thymic selection produces a repertoire that is very "bumpy," with marked overrepresentation of a subset of sequences; (2) MHC class I- and class II-restricted TCRs can be distinguished by minute, single-residue changes in CDR3alpha; and (3) homeostatic expansion and survival in the periphery can markedly remold the postselection repertoire, likely reflecting variability in the potential of cells displaying different TCRs to respond to homeostatic cues.


Subject(s)
Receptors, Antigen, T-Cell, alpha-beta/immunology , T-Lymphocytes/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, T-Cell, alpha-beta/genetics , Thymus Gland/cytology , Thymus Gland/immunology
11.
Curr Opin Immunol ; 12(6): 661-3, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11102769
12.
Eur J Immunol ; 30(10): 2980-90, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11069081

ABSTRACT

While performing a large-scale analysis of mRNA transcripts in the murine thymus, our attention was drawn to the forkhead family transcription factor FKHR. Here we demonstrate that FKHR is expressed in thymocytes, most prominently in those that are undergoing positive selection. Interestingly, FKHR transcripts show a highly regionalized pattern of expression, concentrated in the innermost areas of the medulla. We define the FKHR binding site as (G/C)(A/C)N(G/a)T(A/c)AA(T/c) A(T/g)(T/g)(G/c), a sequence found in the regulatory elements of many genes, including certain that encode molecules crucial for thymocyte differentiation. To study the function of FKHR, we engineered mice expressing a dominant-negative mutant specifically in T cells in a tetracycline-regulatable fashion. In these animals, T cell differentiation appeared quite normal; however, total thymocyte numbers were decreased, owing to reductions in all four of the CD4/CD8 subsets, and incorporation of the thymidine analogue bromo-deoxyuridine was increased, again in all four subsets. These data suggest that, in thymocytes, FKHR may be involved in cell survival and/or cycling.


Subject(s)
DNA-Binding Proteins/physiology , Gene Expression Regulation, Developmental , T-Lymphocyte Subsets/cytology , Thymus Gland/cytology , Transcription Factors/physiology , Animals , Binding Sites , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation , Clonal Deletion , Forkhead Box Protein O1 , Forkhead Transcription Factors , Genes, Dominant , Lymphocyte Count , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mice, Transgenic , RNA, Messenger/biosynthesis , Recombinant Fusion Proteins/genetics , Regulatory Sequences, Nucleic Acid
13.
Arthritis Res ; 2(2): 90-4, 2000.
Article in English | MEDLINE | ID: mdl-11094418

ABSTRACT

Dominant paradigms for the understanding of rheumatoid arthritis (RA) pathogenesis have changed over the years. A predominant role of B lymphocytes, and perhaps of the rheumatoid factor they produced, was initially invoked. In more recent years, recognition of antigens in the joint by T cells sparking an inflammatory cascade has been a more favored interpretation. Here, we re-examine some of the arguments that underpin this proposed role of joint T cells, in light of recent results from transgenic mice in which a self-reactive T-cell receptor provokes disease, but from outside the joint and indirectly via B lymphocytes and immunoglobulins.


Subject(s)
Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/physiopathology , B-Lymphocytes/immunology , Disease Models, Animal , T-Lymphocytes/immunology , Animals , B-Lymphocytes/cytology , Humans , Immunoglobulins/immunology , Major Histocompatibility Complex/immunology , Mice , Mice, Transgenic , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/cytology
14.
J Immunol Methods ; 245(1-2): 133-7, 2000 Nov 01.
Article in English | MEDLINE | ID: mdl-11042290

ABSTRACT

A plasmid cassette vector was designed to generate transgenic mice expressing reporter cDNAs at high levels in antigen-presenting cells under the control of the murine invariant chain (Ii) promoter. Analysis of several transgenic mice harboring a chimeric Ii cDNA placed in this vector showed that it can drive expression of the reporter protein to levels comparable to those of endogenous Ii. Furthermore, its expression pattern overlaps quite well with that of endogenous Ii. This vector should therefore be a convenient and versatile tool for the generation of transgenic mouse lines in which a desired protein may be expressed in Ii-positive cells at levels similar to those of endogenous Ii. Such a vector would be ideal for complementation studies of Ii-deficiency by specific Ii variants.


Subject(s)
Antigens, Differentiation, B-Lymphocyte/genetics , Genes, Reporter , Genetic Vectors , Histocompatibility Antigens Class II/genetics , Promoter Regions, Genetic , Animals , Antigen-Presenting Cells/immunology , Antigens, Differentiation, B-Lymphocyte/biosynthesis , Cytochrome c Group/biosynthesis , Cytochrome c Group/genetics , DNA, Complementary/genetics , Gene Expression , Histocompatibility Antigens Class II/biosynthesis , Histocompatibility Antigens Class II/metabolism , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plasmids/genetics , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Spleen/immunology , Spleen/metabolism , Thymus Gland/immunology , Thymus Gland/metabolism
15.
Proc Natl Acad Sci U S A ; 97(22): 12204-9, 2000 Oct 24.
Article in English | MEDLINE | ID: mdl-11035773

ABSTRACT

Engagement of the T cell costimulatory receptor CTLA-4 can potently down-regulate an immune response. For example, in a T cell receptor transgenic mouse model of autoimmune diabetes, CTLA-4 interactions keep pancreatic islet-reactive T cells in check, evidenced by the finding that mAb blockade of CTLA-4 rapidly provokes diabetes in animals that would not normally succumb until many months later. Interestingly, this effect is only observed early in the course of disease, before insulitis is stably entrenched. Here, we have exploited a highly synchronous and easily manipulable transfer system to determine precisely when CTLA-4 must be engaged to check the diabetogenicity of islet-reactive T cells. Our results indicate that CTLA-4 interactions during initial priming of the T cells in the pancreatic lymph nodes are not determinant. Rather, the critical interactions occur when the T cells secondarily reencounter their antigen in the target organ, the pancreatic islets. In addition, we made use of CTLA-4-deficient mice to bolster our interpretation that CTLA-4 engagement has a dampening rather than an enhancing influence on diabetes progression.


Subject(s)
Antigens, Differentiation/immunology , Diabetes Mellitus, Type 1/immunology , Immunoconjugates , T-Lymphocytes/immunology , Abatacept , Animals , Antibodies, Monoclonal/immunology , Antigens, CD , CTLA-4 Antigen , Disease Models, Animal , Lymph Nodes/immunology , Mice , Mice, Transgenic , Pancreas/immunology
16.
Hum Mol Genet ; 9(5): 813-9, 2000 Mar 22.
Article in English | MEDLINE | ID: mdl-10749989

ABSTRACT

H-TWIST belongs to the family of basic helix-loop-helix (bHLH) transcription factors known to exert their activity through dimer formation. We have demonstrated recently that mutations in H-TWIST account for Saethre-Chotzen syndrome (SCS), an autosomal dominant craniosynostosis syndrome characterized by premature fusion of coronal sutures and limb abnormalities of variable severity. Although insertions, deletions, nonsense and missense mutations have been identified, no genotype-phenotype correlation could be found, suggesting that the gene alterations lead to a loss of protein function irrespective of the mutation. To assess this hypothesis, we studied stability, dimerization capacities and subcellular distribution of three types of TWIST mutant. Here, we show that: (i) nonsense mutations resulted in truncated protein instability; (ii) missense mutations involving the helical domains led to a complete loss of H-TWIST heterodimerization with the E12 bHLH protein in the two-hybrid system and dramatically altered the ability of the TWIST protein to localize in the nucleus of COS-transfected cells; and (iii) in-frame insertion or missense mutations within the loop significantly altered dimer formation but not the nuclear location of the protein. We conclude that at least two distinct mechanisms account for loss of TWIST protein function in SCS patients, namely protein degradation and subcellular mislocalization.


Subject(s)
Cell Nucleus/metabolism , Craniosynostoses/genetics , Mutation , Nuclear Proteins/genetics , Transcription Factors , Animals , COS Cells , Genotype , Hydrolysis , Nuclear Proteins/metabolism , Phenotype , Twist-Related Protein 1 , Two-Hybrid System Techniques
18.
J Exp Med ; 191(2): 355-64, 2000 Jan 17.
Article in English | MEDLINE | ID: mdl-10637279

ABSTRACT

A system that allows the study, in a gentle fashion, of the role of MHC molecules in naive T cell survival is described. Major histocompatibility complex class II-deficient mice were engineered to express Ealpha chains only in thymic epithelial cells in a tetracycline (tet)-controllable manner. This resulted in tet-responsive display of cell surface E complexes, positive selection of CD4(+)8(-) thymocytes, and generation of a CD4(+) T cell compartment in a class II-barren periphery. Using this system, we have addressed two unresolved issues: the half-life of naive CD4(+) T cells in the absence of class II molecules (3-4 wk) and the early signaling events associated with class II molecule engagement by naive CD4(+) T cells (partial CD3 zeta chain phosphorylation and ZAP-70 association).


Subject(s)
Bacterial Proteins/metabolism , CD4-Positive T-Lymphocytes/cytology , Carrier Proteins , Histocompatibility Antigens Class II/physiology , Repressor Proteins/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , CD4-Positive T-Lymphocytes/drug effects , Cell Differentiation , Cell Survival , Gene Expression Regulation , Histocompatibility Antigens Class II/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Repressor Proteins/genetics , Tetracycline/pharmacology
20.
J Immunol ; 163(10): 5471-7, 1999 Nov 15.
Article in English | MEDLINE | ID: mdl-10553073

ABSTRACT

Some TCR variable regions are preferentially expressed in CD4+ or CD8+ T cells, reflecting a predilection for interacting with MHC class II or class I molecules. The molecular basis for MHC class bias has been studied previously, in particular for V alpha 3 family members, pointing to a dominant role for two amino acid positions in complementary-determining regions (CDRs) 1 and 2. We have evaluated the generality of these findings by examining the MHC class bias of V alpha 2 family members, an attractive system because it shows more variability within the CDR1 and -2, exhibits variation in the framework regions, and includes a member for which the crystal structure has been determined. We find that preferential recognition of MHC class I or II molecules does not always depend on residues at the same positions of CDR1 and -2; rules for one family may be reversed in another. Instead, there are multiple influences exerted by various CDR1/2 positions as well as the CDR3s of both the TCR alpha- and TCR beta-chains.


Subject(s)
Amino Acid Substitution/immunology , Histocompatibility Antigens Class II/metabolism , Histocompatibility Antigens Class I/metabolism , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Amino Acid Substitution/genetics , Animals , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Egg Proteins/genetics , Egg Proteins/metabolism , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/metabolism , Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Molecular , Multigene Family/immunology , Ovalbumin/genetics , Ovalbumin/metabolism , Peptide Fragments/biosynthesis , Peptide Fragments/genetics , Peptide Fragments/metabolism , Receptors, Antigen, T-Cell, alpha-beta/biosynthesis , Receptors, Antigen, T-Cell, alpha-beta/genetics
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