BackgroundThe importance of CD4+ and CD8+ T cells in protection against tuberculosis (TB) is well known, however, the association between changes to the T cell repertoire and disease presentation has never been analyzed. Characterization of T-cells in TB patients in previous study only analyzed the TCR β chain and omitted analysis of the Vα family even though α chain also contribute to antigen recognition. Furthermore, limited information is available regarding the heterogeneity compartment and overall function of the T cells in TB patients as well as the common TCR structural features of Mtb antigen specific T cells among the vast numbers of TB patients.Methodology/Principal FindingsCDR3 spectratypes of CD4+ and CD8+ T cells were analyzed from 86 patients with TB exhibiting differing degrees of disease severity, and CDR3 spectratype complexity scoring system was used to characterize TCR repertoire diversity. TB patients with history of other chronic disease and other bacterial or viral infections were excluded for the study to decrease the likely contribution of TCRs specific to non-TB antigens as far as possible. Each patient was age-matched with a healthy donor group to control for age variability. Results showed that healthy controls had a normally diversified TCR repertoire while TB patients represented with restricted TCR repertoire. Patients with mild disease had the highest diversity of TCR repertoire while severely infected patients had the lowest, which suggest TCR repertoire diversity inversely correlates with disease severity. In addition, TB patients showed preferred usage of certain TCR types and have a bias in the usage of variable (V) and joining (J) gene segments and N nucleotide insertions.Conclusions/SignificanceResults from this study promote a better knowledge about the public characteristics of T cells among TB patients and provides new insight into the TCR repertoire associated with clinic presentation in TB patients.
Cell-mediated immunity is critical to the clearance of Mycobacterium tuberculosis due to the primarily intracellular niche of this pathogen. Adoptive transfer of M. tuberculosis-specific effector T cells has been shown to confer immunity to M. tuberculosis-infected recipients resulting in M. tuberculosis clearance. However, it is difficult to generate sufficient numbers of M. tuberculosis antigen-specific T cells in a short time. Recent studies have developed T cell receptor (TCR) gene-modified T cells that allow for the rapid generation of large numbers of antigen-specific T cells. Many TCRs that target various tumor and viral antigens have now been isolated and shown to have functional activity. Nevertheless, TCRs specific for intracellular bacterial antigens (including M. tuberculosis antigens) have yet to be isolated and their functionality confirmed. We isolated M. tuberculosis 38-kDa antigen-specific HLA class I and class II-restricted TCRs and modified the TCR gene C regions by substituting nine amino acids with their murine TCR homologs (minimal murinization). Results showed that both wild-type and minimal murinized TCR genes were successfully cloned into retroviral vectors and transduced into primary CD4(+) and CD8(+) T cells and displayed anti-M. tuberculosis activity. As expected, minimal murinized TCRs displayed higher cell surface expression levels and stronger anti-M. tuberculosis activity than wild-type TCRs. To the best of our knowledge, this is the first report describing TCRs targeting M. tuberculosis antigens and this investigation provides the basis for future TCR gene-based immunotherapies that can be designed for the treatment of immunocompromised M. tuberculosis-infected patients.
IntroductionThe invariant natural killer T (iNKT) cell has been shown to play a central role in early stages immune responses against Mycobacterium tuberculosis (Mtb) infection, which become nonresponsive (anergic) and fails to control the growth of Mtb in patients with active tuberculosis. Enhancement of iNKT cell responses to Mtb antigens can help to resist infection.Study design and methodsIn the present study, an Mtb 38-kDa antigen-specific T cell receptor (TCR) was isolated from human CD8+ T cells stimulated by 38-kDa antigen in vitro, and then transduced into primary iNKT cells by retrovirus vector.ResultsThe TCR gene-modified iNKT cells are endowed with new features to behave as a conventional MHC class I restricted CD8+ T lymphocyte by displaying specific antigen recognition and anti-Mtb antigen activity in vitro. At the same time, the engineered iNKT cells retaining its original capacity to be stimulated proliferation by non-protein antigens α-Gal-Cer.ConclusionsThis work is the first attempt to engineer iNKT cells by exogenous TCR genes and demonstrated that iNKT cell, as well as CD4+ and CD8+ T cells, can be genetically engineered to confer them a defined and alternative specificity, which provides new insights into TCR gene therapy for tuberculosis patients, especially those infected with drug-resistant Mtb.
The nerve trunk healing process of a transected peripheral nerve trunk is composed of angiogenesis, nerve fiber regeneration, and scarring. Nerve trunk healing and neuroma formation probably share identical molecular mediators and similar regulations. At the nerve transection site, angiogenesis is sufficient and necessary for nerve fiber regeneration. Angiogenesis and nerve fiber regeneration reveal a positive correlation in the early time. Scarring and nerve fiber regeneration show a negative correlation in the late phase. We hypothesize that anti-angiogenesis suppresses neuromas. Subsequently, we provide potential protocols to test our hypothesis. Finally, we recommend employing anti-angiogenic small-molecule protein kinase inhibitors to investigate nerve transection injuries.
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