RESUMO
BACKGROUND: Advanced stages of leprosy show T cell unresponsiveness and lipids of mycobacterial origin are speculated to modulate immune responses in these patients. Present study elucidates the role of phenolicglycolipid (PGL-1) and Mannose-capped lipoarabinomannan (Man-LAM) on TCR- and TCR/CD28- mediated signalling. RESULTS: We observed that lipid antigens significantly inhibit proximal early signalling events like Zap-70 phosphorylation and calcium mobilization. Interestingly, these antigens preferentially curtailed TCR-triggered early downstream signalling events like p38 phosphorylation whereas potentiated that of Erk1/2. Further, at later stages inhibition of NFAT binding, IL-2 message, CD25 expression and T-cell blastogenesis by PGL-1 and Man-LAM was noted. CONCLUSION: Altogether, we report that Man-LAM and PGL-1 preferentially interfere with TCR/CD28-triggered upstream cell signalling events, leading to reduced IL-2 secretion and T-cell blastogenesis which potentially could lead to immunosupression and thus, disease exacerbation, as noted in disease spectrum.
Assuntos
Antígenos de Bactérias/farmacologia , Antígenos CD28/fisiologia , Glicolipídeos/farmacologia , Lipopolissacarídeos/farmacologia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia , Antígenos de Bactérias/imunologia , Antígenos CD28/metabolismo , Sinalização do Cálcio , Proliferação de Células , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Glicolipídeos/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Celular , Interleucina-2/genética , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Células Jurkat , Hanseníase/imunologia , Hanseníase/microbiologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/microbiologia , Lipopolissacarídeos/imunologia , Ativação Linfocitária , Sistema de Sinalização das MAP Quinases , Mycobacterium leprae/imunologia , Fatores de Transcrição NFATC/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Ligação Proteica , Proteína Quinase C/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/microbiologia , Proteína-Tirosina Quinase ZAP-70/metabolismoRESUMO
We investigated the role of Mycobaterium leprae soluble antigen (MLSA) in the modulation of calcium signalling, phosphorylation of mitogen-activated protein (MAP) kinases and IL-2 mRNA expression in human Jurkat T cells. We observed that MLSA induced an increase in free intracellular calcium concentrations, [Ca2+]i, via opening CRAC (Ca2+-release activated- Ca2+) channels. Furthermore, MLSA failed to potentiate both thapsigargin- and anti-CD3 antibodies-induced capacitative calcium influx in Jurkat T cells. We observed that MLSA failed to affect the degree of phosphorylation of two MAP kinases, i.e., ERK1/ERK2, stimulated by anti-CD3 antibodies alone or phorbol 12-myristate 13-acetate (PMA) alone. In order to mimic co-stimulation of T cells, we stimulated them by both PMA and anti-CD3 antibodies. MLSA significantly curtailed the phosphorylation of ERK1/ERK2, stimulated by both PMA and anti-CD3 antibodies in Jurkat T cells. Also MLSA was found to reduce the transcription of IL-2 gene in PMA plus anti-CD3 antibodies-activated Jurkat T cells. Our finding demonstrates that Ca2+ influx via CRAC channels, inhibition of ERK1/ERK2 phosphorylation and IL-2 gene transcription may be implicated in immunosuppressive effects of MLSA antigen.