Clonal dominance and selection for similar complementarity determining region 3 motifs among T lymphocytes responding to the HLA-DR3-associated Mycobacterium leprae heat shock protein 65-KD peptide 3–13

Struyk, Linda; Hawes, Gail E.; Haanen, John B.A.G.; Vries, RenéR.P. de; Elsen, Peter J. van den

doi:10.1016/0198-8859(95)00110-7

Cited by 17 publications

(17 citation statements)

References 40 publications

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“…Response to M. leprae infection can therefore be said to rely largely on the HLA-DR motif presenting the peptide to T cells with specific CDR3 motifs on the T cell. Data from other workers [29,31] also support this conclusion.…”

Section: Discussionsupporting

confidence: 64%

HLA-DRB1 leprogenic motifs in Nigerian population groups

et al. 1999

Clinical and Experimental Immunology

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SUMMARYAmino acid residues involved in the peptide binding groove of HLA-DRB1 alleles were examined in three Nigerian ethnic groups with leprosy (n ¼ 287) and 170 controls to determine the role of DRB1 alleles in disease outcome with Mycobacterium leprae. Nine positively charged motifs and two others with neutral charge to the binding groove were detected. These motifs occurred more frequently in leprosy (leprogenic) than was expected by chance (P < 0·0001). In contrast, five motifs with net negative or 'modified' neutral charges to the pocket were negatively associated with leprosy. We conclude that clinical outcome of infection with M. leprae is largely determined by a shared epitope in DRB1 alleles marked by several motifs. These motifs occur in otherwise normal DRB1 alleles, characterized by net positive or neutral charges in the binding groove. We hypothesize that these polarities cause poor binding of DRB1 to M. leprae. On presentation, the signal via the T cell receptor results in muted cellmediated immunity. The resulting response translates to various forms of leprosy depending on degree of charge consonance between M. leprae and host DRB1 allele. Other factors within or without the HLA complex, such as the T cell receptor repertoire, may also influence the resulting disease.

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Section: Discussionsupporting

confidence: 64%

HLA-DRB1 leprogenic motifs in Nigerian population groups

et al. 1999

Clinical and Experimental Immunology

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“…In tuberculoid leprosy patients, T cells bearing TCR V␤ family 6 are overrepresented in lesions but not in the peripheral blood (34,35). M. bovis hsp65 peptide-specific T-cell clones express more TCR V␤ families 5.1 and J␣ 9 (15,31). Previous studies of cytokine expression in the peripheral blood of tuberculosis patients and endemic controls have shown that there is PPD-specific enhancement or suppression of gamma interferon and IL-10 following 48 h of culture (7).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium bovisBCG Scar Status and HLA Class II Alleles Influence Purified Protein Derivative-Specific T-Cell Receptor Vβ Expression in Pulmonary Tuberculosis Patients from Southern India

Shanmugalakshmi¹,

Dheenadhayalan²,

Muthuveeralakshmi

et al. 2003

Infect Immun

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Purified protein derivative (PPD) RT23-recalled T-cell receptor (TCR) V␤ expression was studied in the peripheral blood of 42 pulmonary tuberculosis patients and 44 healthy controls from southern India, a region where tuberculosis is endemic. Forty-eight-hour whole-blood cultures in the presence or absence of PPD-RT23 were set up, and at the end of the culture period total RNA was extracted and cDNA was synthesized. Expression of various TCR V␤ families was assessed by using family-specific primers. PPD-specific expression (usage) of TCR V␤ families 4, 6, 8 to 12, and 14 was found in more controls than patients. Among the responders (individuals who showed PPD-specific expression), endemic controls had significantly higher responses than the patients had for TCR V␤ families 2, 3, 7, 13, and 17. The majority of the patients did not show usage of most of the TCR V␤ families, and this was attributed to T-cell downregulation. A four-way nested classification analysis revealed that TCR V␤ family 1, 5, 9, 12, and 13 usage in the context of HLA class II high-risk alleles (DRB1*1501, DRB1*08, and DQB1*0601) and Mycobacterium bovis BCG scar status were the determining factors in susceptibility and resistance to tuberculosis. The healthier status of controls was attributed to the wider usage of many TCR V␤ families readily recalled by PPD, while the disease status of the patients was attributed to TCR V␤ downregulation and the resultant T-cell (memory cell?) unresponsiveness. Host genetics (HLA status) and BCG vaccination (scar status) seem to play important roles in skewing the immune response in adult susceptibility to pulmonary tuberculosis through TCR V␤ usage.

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“…Antigen-specific T-cell lines were generated from peripheral blood mononuclear cells (PBMC) of four HLA-DR3 (17)-expressing healthy donors using BCG at 5 mg/ml or peptide (hsp 65 aa 3-13) at 5 mg/ml as described previously (Struyk et al 1996). T-cell lines were cloned by limiting dilution after 14 days of initial stimulation.…”

Section: Antigen-specific T-cell Lines and Clonesmentioning

confidence: 99%

“…To search for additional TCR sequences in the oligoclonal T-cell line from the leprosy patient (R), the TRBV5 PCR product from the hsp65 aa 3-13-specific T-cell line was amplified by reverse transcriptase-PCR and the product was cloned into a bacterial vector for screening as previously described (Struyk et al 1996). The obtained bacterial clones were screened by hybridization with the CDR3-specific, g [ 32 P]-ATP end-labeled oligonucleotide : 5b-TTT GGC CAG TCC AAT GAG-3b (plas R1; see Fig.…”

Section: Bacterial Cloning Sequencing and Colony Screening Of Trbv5mentioning

confidence: 99%

“…Recently, we have shown that an MHC class II/peptide complex is also capable of selecting T cells possessing the same TRBV gene and having similar CDR3 regions (Struyk et al 1996;Van Schooten et al 1992). This was seen in a tuberculoid leprosy patient, by analyzing the response to a DR3 (17)-restricted peptide aa 3-13 from the mycobacterial M r 65 000 heat shock protein (hsp65) which yielded an overwhelming response of TRBV5 with a conserved aa motif recurring in the CDR3 region.…”

Section: Introductionmentioning

confidence: 99%

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Conserved TcR β chain usage for a single MHC class II-restricted heat shock protein peptide

et al. 1998

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Previously we have shown that the T-cell response against the HLA-DR3 (17)-restricted heat shock protein (Mr 65 000)-derived peptide amino acids (aa) 3-13 (hsp65 aa 3-13) is recognized by the exclusive usage of the TRBV5 gene as well as a conserved CDR3 region in a tuberculoid leprosy patient. In the present study we analyzed the TcR of T-cell clones specific for hsp65 aa 3-13 derived from three healthy individuals with a response level similar to that of the leprosy patient. We show that unlike the tuberculoid leprosy patient, healthy high responders have a diverse T-cell response to hsp65 aa 3-13. However, a striking observation was made: even though high responders have a diverse specific TcR repertoire, TRBV5-expressing clones from two healthy individuals could be isolated that were nearly identical to a dominant clone in the tuberculoid leprosy patient. In conclusion, the data show that restriction of TcR specific for an antigen correlates with the presence of that antigen in disease. However, the preferred TcR can also be detected in healthy high responders. A natural infection in vivo, as with the tuberculoid leprosy patient, may be responsible for the observed trimming and preferential outgrowth of a certain TcR.

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Clonal dominance and selection for similar complementarity determining region 3 motifs among T lymphocytes responding to the HLA-DR3-associated Mycobacterium leprae heat shock protein 65-KD peptide 3–13

Cited by 17 publications

References 40 publications

HLA-DRB1 leprogenic motifs in Nigerian population groups

HLA-DRB1 leprogenic motifs in Nigerian population groups

Mycobacterium bovisBCG Scar Status and HLA Class II Alleles Influence Purified Protein Derivative-Specific T-Cell Receptor Vβ Expression in Pulmonary Tuberculosis Patients from Southern India

Conserved TcR β chain usage for a single MHC class II-restricted heat shock protein peptide

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