First discovered in the 1980's, granulysin has until recently been thought of solely as an effector molecule present within cytotoxic immune cell populations, and involved in the direct killing of pathogens and infected or transformed eukaryotic cells. However, recent research has suggested an additional role of granulysin, in particular the 15 kDa isoform. While 9 kDa granulysin is broadly cytotoxic and capable of the direct killing of bacteria and other pathogens, the 15 kDa isoform of this molecule has been shown to function as an immune 'alarmin', causing the maturation and migration of antigen-presenting cells and other cells of the immune system. This dual function of granulysin indirectly increases the immune response to an infection or tumour, and therefore escalates its importance in the immune system. Here we review the different roles of granulysin, both as a cytotoxic molecule, and as a modulator of the immune system, and discuss the impact this molecule may have on the response to tumour and infection.

Background The major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred as GABA(A) receptors (GABA(A)R). Recent evidence indicates a role of GABA(A)R in modulating the immune response. This work aimed to discern the role of GABA and GABA(A)Rs in human and mouse T cell activity. Methods Mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 antibodies and the proliferation of both CD8+ and CD4+ T cells assessed through flow cytometry. Subsequently, the effects on T cell proliferation of either GABA(A)R modulation by diazepam that is also capable of activating mitochondrial based translocator protein (TSPO), alprazolam and allopregnanolone or inhibition by bicucculine methiodide (BMI) and (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) were assessed. Results Positive modulation of GABA(A)Rs either by benzodiazepines or the neurosteroid allopregnanolone inhibits both mouse and human T cell proliferation. GABAergic inhibition of T cell proliferation by benzodiazepines could be rescued by GABA(A)R blocking. Our data suggest that benzodiazepines influence T cell proliferation through both TSPO and GABA(A)Rs activation. Conclusions We conclude that activation of GABA(A)Rs provides immunosuppression by inhibiting T cell proliferation.

Release of granulysin by cd T cells contributes to tumour cell killing. A cytolytic 9000 MW isoform of granulysin kills tumour cells directly, whereas a 15 000 MW precursor has been hypothesized to cause both the maturation and migration of dendritic cell (DC) populations. Recruiting DC to a tumour is beneficial as these cells initiate adaptive immune responses, which contribute to the eradication of malignancies. In this study, Vd2 + cd T cells were activated by stimulation of peripheral blood mononuclear cells with zoledronic acid or Bacillus Calmette-Gu erin (BCG), or were isolated and cultured with tumour targets. Although a large proportion of resting Vd2 + cd T cells expressed 15 000 MW granulysin, 9000 MW granulysin expression was induced only after stimulation with BCG. Increased levels of activation and granulysin secretion were also observed when Vd2 + cd T cells were cultured with the human B-cell lymphoma line Daudi. High concentrations of recombinant 15 000 MW granulysin caused migration and maturation of immature DC, and also initiated fugetaxis in mature DC. Conversely, low concentrations of recombinant 15 000 MW granulysin resulted in migration of mature DC, but not immature DC. Our data therefore support the hypothesis that Vd2 + cd T cells can release granulysin, which may modulate recruitment of DC, initiating adaptive immune responses.