Synovial fluid T cell clones from oligoarticular juvenile arthritis patients display a prevalent Th1/Th0-type pattern of cytokine secretion irrespective of immunophenotype

Mycobacteria elicit a cellular immune response in their hosts. This response usually leads to protective immunity, but may sometimes be accompanied by immunopathology due to delayed type hypersensitivity (DTH). A striking example in man is tuberculoid leprosy, which is characterized by high cellular immunity to Mycobacterium leprae and immunopathology due to DTH. Skin lesions of patients suffering from this disease have the characteristics of DTH reactions in which macrophages and CD4+ T lymphocytes predominate. In animal models, it has been shown that DTH responses are associated with the presence of a particular subset of CD4+ T cells (T helper type 1 [Th1]) that secrete only certain cytokines, such as interleukin 2 (IL-2), interferon gamma (IFN-gamma), and lymphotoxin, but no IL-4 or IL-5. We studied the cytokine release of activated M. leprae-reactive CD4+ T cell clones derived from tuberculoid leprosy patients. These T cell clones, which were reactive with mycobacterial heat shock proteins, exhibited a Th1-like cytokine secretion pattern with very high levels of IFN-gamma. Half of these clones secreted low levels of IL-4 and IL-5, but the ratio of IFN-gamma to IL-4 and IL-5 was much higher than that of T cell clones reactive with nonmycobacterial antigens. A Th1-like cytokine secretion pattern was also observed for T cell clones and polyclonal T cell lines from control individuals that recognized both heat shock and other mycobacterial antigens. The levels of IFN-gamma secreted by these clones were, however, significantly less than those of patient-derived T cell clones. This Th1-like pattern was not found with T cell clones from the same patients and healthy individuals generated in the same manner, but reactive with nonmycobacterial antigens. Our data thus indicate that mycobacteria selectively induce human T cells with a Th1-like cytokine secretion profile.

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Recognition of a mycobacteria-specific epitope in the 65-kD heat-shock protein by synovial fluid-derived T cell clones.

Journal of Experimental Medicine ◽

10.1084/jem.171.3.831 ◽

1990 ◽

Vol 171 (3) ◽

pp. 831-841 ◽

Cited By ~ 126

Author(s):

J S Gaston ◽

P F Life ◽

P J Jenner ◽

M J Colston ◽

P A Bacon

Keyword(s):

Amino Acids ◽

T Cell ◽

Heat Shock ◽

Synovial Fluid ◽

Heat Shock Protein ◽

Mononuclear Cells ◽

Cell Clone ◽

T Cell Clones ◽

Cell Clones ◽

T Cell Clone

Adjuvant arthritis in rats is induced by a T cell clone specific for amino acids 180-188 of the mycobacterial 65-kD heat-shock protein, and synovial T cell responses to this same Ag have been noted in human arthritis. We have isolated 65-kD Ag-specific T cell clones from synovial fluid mononuclear cells of a patient with acute arthritis, which, unlike the corresponding PBMC, showed a marked proliferative response to the 65-kD Ag. Using synthetic peptides corresponding to the whole sequence of the 65-kD Ag, all the clones were shown to recognize an epitope present in the first NH2-terminal peptide (amino acids 1-15), with no response to the adjacent peptide (amino acids 6-22) or to any other peptide. The complete dominance of this epitope in the response to the 65-kD Ag was shown by documenting responses to the peptide in PBMC obtained after recovery from the arthritis. This epitope, like that recognized by the rat arthritogenic T cell clone, is in a portion of the 65-kD sequence that is not conserved between bacteria and eukaryotes, so that in this case, joint inflammation could not be attributed to bacteria-induced T cell clones cross-reacting with the self 65-kD Ag.

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OP0027 AS-RELATED TCR BETA CLONOTYPES ARE PRESENT IN DIFFERENT INFLAMED TISSUES OF PATIENTS WITH SPONDYLOARTHROPATHIES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3535 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 14.3-15

Author(s):

E. Komech ◽

A. Barinova ◽

E. Shmidt ◽

T. Korotaeva ◽

A. Koltakova ◽

...

Keyword(s):

T Cells ◽

Psoriatic Arthritis ◽

Ankylosing Spondylitis ◽

T Cell ◽

Synovial Fluid ◽

Intestinal Inflammation ◽

T Cell Repertoire ◽

Cell Repertoire ◽

T Cell Clones ◽

Cell Clones

Background:Recently a group of T-cell clones with characteristic T-cell receptor (TCR) motif was identified in peripheral blood and synovial fluid of HLA-B*27+ patients with ankylosing spondylitis (AS) [1-2] - a prototypic disease from a wider group of spondyloarthropathies (SpAs). Extraarticular manifestations of AS could involve skin, intestine or eye. Emerging data indicate linkage between intestinal and joint inflammation, including expression of gut-associated integrins on synovial T-cells [3-4]. However, clonal T-cell composition and presence of identical clones in different inflamed sites in SpAs remains poorly studied.Objectives:To investigate clonal T-cell repertoire and presence of AS-related TCR motif in different sites of inflammation of patients with SpA.Methods:Samples of synovial fluid (SF) were obtained from HLA-B*27+ and HLA-B*27- patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA), as well as gut biopsy samples from patients with AS and Crohn’s disease (AS/CD) or ulcerative colitis (AS/UC), and conjunctival swabs from patients with uveitis (Uv) and with or without articular manifestations (Table 1). Also SF and gut biopsy samples were obtained from HLA-B*27+ patients with juvenile idiopathic arthritis (JIA). For one patient PsA patient paired samples of SF and gut biopsy were obtained.Table 1.Detection of the AS-related motif TRBV9_CASS[V/A/L/P][G/A] [L/T/V][F/Y]STDTQYF_TRBJ2-3 in bTCR repertoires of samples from different inflamed sites of patients with SpATissueDiagnosisB27+B27-AS-related TCR motif+ among all samples from B27+ donorsSynovial fluidAS2012PsAJIAIntestinal biopsyAS/CD433 / 4AS/UCJLAConjunctival swabUv804 / 8SF and gut samples were processed to isolate mononuclear cells, while conjunctival swabs were directly lysed in the lysis buffer. CD3+ β7-intergin+ cells were isolated from SF by fluorescence-activated cell sorting. Deep TCR repertoire profiling was carried out using UMI-based cDNA library preparation technology [1].Results:Identical T-cell clonotypes were detected between paired SF and gut samples of the same patient with psoriatic arthritis and intestinal inflammation. The subpopulation of β7-intergin+ SF T-cells shared significantly more identical clonotypes with gut biopsy repertoire compared to the bulk SF T-cell repertoire.Clonotypes belonging to the AS-related TCR beta motif TRBV9_CASS[V/A/L/P][G/A][L/T/V][F/Y]STDTQYF_TRBJ2-3 were detected in all inflamed tissues tested: synovial fluid, intestinal biopsies and conjunctival swabs of SpA patients (Table 1). Importantly, we observed these clonotypes exclusively in samples from HLA-B*27+ donors (n=26), but not in HLA-B27- context (n=15) with comparable analysis depth, thus confirming strong HLA-B*27-restriction of the clonotypes. The AS-related clonotypes were detected in the subpopulation of β7-intergin+ SF T-cells from HLA-B*27+ patients with PsA.Conclusion:For the first time we directly report the T-cell clonal sharing between synovial fluid and inflamed gut tissue of SpA patients. In sum our data suggests involvement of identical T-cell clones in inflammation in different anatomical sites in SpA.References:[1]Komech et al. Rheumatology (Oxford). 2018;57(6):1097-1104.[2]Faham et al. Arthritis Rheumatol. 2016;11(10):300-308.[3]Guggino et al.Ann Rheum Dis. Published Online First: 18 October 2019.doi:10.1136/annrheumdis-2019-216456.[4]Qaiyum et al Ann Rheum Dis. 2019;78(11):1566-1575.Acknowledgements:We thanks all the patients and medical personnel involved in the studyDisclosure of Interests:None declared

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