Cross-reactive epitopes and HLA-restriction elements in human T cell recognition of the<i>Mycobacterium leprae</i>18-kD heat shock protein

Mustafa, Abu Salim; Lundin, Knut E.A.; Meloen, R. H.; Oftung, Fredrik

doi:10.1046/j.1365-2249.2000.01156.x

Cited by 14 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2) or by vaccination with a live, attenuated strain, suggesting that even mild infection can induce a committed effector response. Responses against PPD in our subjects were induced either by vaccination with bacillus Calmette-Guerin live vaccine, or presumably by subclinical infection with environmental mycobacteria-expressing Ags that crossreact with PPD (17)(18)(19). Thus, we conclude that in most or all of the subjects, the IFN-␥-dominated CD4 T cell responses against RSV proteins, inactivated influenza and mumps virus, and mycobacterial Ag PPD were initially primed by live infections.…”

Section: Discussionmentioning

confidence: 80%

“…As the incidence of influenza infection is 5-20% per year, most or all would have been primed by infection before adult vaccination. Two of the fifteen individuals had been vaccinated with live bacillus Calmette-Guerin, and additional subjects may have been primed by subclinical infection with cross-reactive mycobacteria (17)(18)(19). Thirteen of the individuals received live, attenuated mumps vaccine in childhood, and the other two had a history of mumps infection.…”

Section: Vaccination and Infection History Of Subjectsmentioning

confidence: 99%

See 1 more Smart Citation

Protein Vaccines Induce Uncommitted IL-2-Secreting Human and Mouse CD4 T Cells, Whereas Infections Induce More IFN-γ-Secreting Cells

Divekar

Zaiss

Lee

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

Mouse and human CD4 T cells primed during an immune response may differentiate into effector phenotypes such as Th1 (secreting IFN-γ) or Th2 (secreting IL-4) that mediate effective immunity against different classes of pathogen. However, primed CD4 T cells can also remain uncommitted, secreting IL-2 and chemokines, but not IFN-γ or IL-4. We now show that human CD4 T cells primed by protein vaccines mostly secreted IL-2, but not IFN-γ, whereas in the same individuals most CD4 T cells initially primed by infection with live pathogens secreted IFN-γ. We further demonstrate that many tetanus-specific IL-2+IFN-γ− cells are uncommitted and that a single IL-2+IFN-γ− cell can differentiate into Th1 or Th2 phenotypes following in vitro stimulation under appropriate polarizing conditions. In contrast, influenza-specific IL-2+IFN-γ− CD4 cells maintained a Th1-like phenotype even under Th2-polarizing conditions. Similarly, adoptively transferred OTII transgenic mouse T cells secreted mainly IL-2 after priming with OVA in alum, but were biased toward IFN-γ secretion when primed with the same OVA peptide presented as a pathogen Ag during live infection. Thus, protein subunit vaccines may prime a unique subset of differentiated, but uncommitted CD4 T cells that lack some of the functional properties of committed effectors induced by infection. This has implications for the design of more effective vaccines against pathogens requiring strong CD4 effector T cell responses.

show abstract

Section: Discussionmentioning

confidence: 80%

Section: Vaccination and Infection History Of Subjectsmentioning

confidence: 99%

Protein Vaccines Induce Uncommitted IL-2-Secreting Human and Mouse CD4 T Cells, Whereas Infections Induce More IFN-γ-Secreting Cells

Divekar

Zaiss

Lee

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Recognition of mycobacterial antigens by CD4+ T cells circulating in peripheral blood is mostly restricted by HLA-DR molecules [36][37][38] . These molecules are highly polymorphic and vary in their frequency of expression in various populations and ethnic groups.…”

Section: Discussionmentioning

confidence: 99%

HLA-Promiscuous Th1-Cell Reactivity of MPT64 (Rv1980c), a Major Secreted Antigen of <i>Mycobacterium tuberculosis</i>, in Healthy Subjects

Mustafa

2009

Med Princ Pract

View full text Add to dashboard Cite

Objective: To determine HLA-promiscuous Th1-cell reactivity of MPT64 (Rv1980c) in healthy humans. Materials and Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy subjects (n = 61) and HLA typed genomically. PBMCs were tested for Th1-cell reactivity (antigen-induced proliferation and interferon-γ secretion) with complex antigens (whole cells, culture filtrate and cell walls) and single secreted antigens (Ag85B, MPT64 and MPB70) of Mycobacterium tuberculosis. In addition, culture-filtrate-induced T-cell lines were established from PBMCs of 14 donors and tested with the above antigens in Th1-cell assays. Furthermore, 3 T-cell lines were tested for cytotoxic activity against MPT64-pulsed monocytes/macrophages, and a T-cell line was analysed for HLA restriction in antigen presentation using anti-HLA class I and class II monoclonal antibodies and HLA-DR-typed antigen-presenting cells. Results: PBMCs showed strong Th1-cell reactivity with all of the complex mycobacterial antigens, whereas MPT64 induced moderate Th1-cell reactivity, which was comparable to the reactivity induced by other previously characterized secreted antigens of M. tuberculosis, i.e. Ag85B and MBP70. Furthermore, HLA heterogeneity of the responding donors suggested that MPT64 was presented to Th1 cells promiscuously. Testing of the T-cell lines confirmed that Th1 cells contributed to the promiscuous antigen-specific reactivity observed with PBMCs and exhibited cytotoxic activity against MPT64-pulsed monocytes/macrophages. In addition, a T-cell line investigated for HLA restriction analysis showed that MPT64 was presented to T cells in association with HLA-DR molecules in a promiscuous manner. Conclusion: MPT64 is promiscuously recognized by human Th1 cells with cytotoxic activity and therefore deserves consideration as a candidate vaccine against tuberculosis in humans.

show abstract

“…M. leprae HSP18 is a major T-cell antigen with immunodominant epitopes. Previous studies revealed that the T-cell epitopes carrying amino acids 1-38 and 41-55 of M. leprae HSP18 were found to be cross-reactive with the M. tuberculosis complex, M. avium and other mycobacteria [24]. This 18-kDa gene is transcriptionally activated during intracellular growth in macrophages and may be involved in the survival of M. leprae within the macrophages [25].…”

Section: Introductionmentioning

confidence: 99%

A S52P mutation in the ‘α‐crystallin domain’ of Mycobacterium leprae HSP18 reduces its oligomeric size and chaperone function

et al. 2013

View full text Add to dashboard Cite

Mycobacterium leprae HSP18 is a small heat shock protein (sHSP). It is a major immunodominant antigen of M. leprae pathogen. Previously, we have reported the existence of two M. leprae HSP18 variants in various leprotic patients. One of the variants has serine at position 52, whereas the other one has proline at the same position. We have also reported that HSP18 having proline at position 52 ( HSP18P 52 ) is a nonameric protein and exhibits chaperone function. However, the structural and functional characterization of wild-type HSP18 having serine at position 52 ( HSP18S 52 ) is yet to be explored. Furthermore, the implications of the S52P mutation on the structure and chaperone function of HSP18 are not well understood. Therefore, we cloned and purified these two HSP18 variants. We found that HSP18S 52 is also a molecular chaperone and an oligomeric protein. Intrinsic tryptophan fluorescence and far-UV CD measurements revealed that the S52P mutation altered the tertiary and secondary structure of HSP18. This point mutation also reduced the oligomeric assembly and decreased the surface hydrophobicity of HSP18, as revealed by HPLC and 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid binding studies, respectively. Mutant protein was less stable against thermal and chemical denaturation and was more susceptible towards tryptic cleavage than wild-type HSP18. HSP18P 52 had lower chaperone function and was less effective in protecting thermal killing of Escherichia coli than HSP18S 52. Taken together, our data suggest that serine 52 is important for the larger oligomerization and chaperone function of HSP18. Because both variants differ in stability and function, they may have different roles in the survival of M. leprae in infected hosts. Abbreviations ACD, a-crystallin domain; bis-ANS, 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid, dipotassium salt; CFU, colony-forming unit; FRET, F€ orster resonance energy transfer; Gu-HCl, guanidine hydrochloride; IPTG, isopropyl thio-b-D-galactoside; MDH, malate dehydrogenase; sHSP, small heat shock protein. Structured digital abstract

show abstract

Cross-reactive epitopes and HLA-restriction elements in human T cell recognition of theMycobacterium leprae18-kD heat shock protein

Cited by 14 publications

References 24 publications

Protein Vaccines Induce Uncommitted IL-2-Secreting Human and Mouse CD4 T Cells, Whereas Infections Induce More IFN-γ-Secreting Cells

Protein Vaccines Induce Uncommitted IL-2-Secreting Human and Mouse CD4 T Cells, Whereas Infections Induce More IFN-γ-Secreting Cells

HLA-Promiscuous Th1-Cell Reactivity of MPT64 (Rv1980c), a Major Secreted Antigen of <i>Mycobacterium tuberculosis</i>, in Healthy Subjects

A S52P mutation in the ‘α‐crystallin domain’ of Mycobacterium leprae HSP18 reduces its oligomeric size and chaperone function

Contact Info

Product

Resources

About