15-18 These genes encode the Munc13-4, syntaxin-11, and Munc18-2 proteins, respectively, which are required for critical steps in lytic granule exocytosis. 13, 14 In addition to PRF1, biallelic mutations in UNC13D, STX11, and STXBP2 are associated with FH元, FHL4, and FHL5, respectively. In addition, milder missense mutations in PRF1 may not cause HLH, but are associated with hematologic malignancies later in life. 10-12 HLH caused by PRF1 mutations is termed familial HLH type 2 (FHL2). 9 HLH is a hyperinflammatory disorder characterized by unremitting fever, splenomegaly, hyperferritinemia, cytopenia, and sometimes hemophagocytosis. Subjects with biallelic nonsense mutations in the gene encoding perforin, PRF1, typically develop hemophagocytic lymphohistiocytosis (HLH) in infancy. Therefore, meticulous comparisons of human CTLs and NK cells may provide insights into shared versus distinct mechanisms regulating their cytolytic and cytokine-mediated effector functions.ĭefects in lymphocyte cytotoxic function are associated with often-fatal diseases. These observations may reflect differences in signaling and regulation. 7, 8 Whereas CTLs form stable contacts with target cells, NK cells are more tentative and form transient contacts inducing less profound Ca 2+ mobilization and cytoskeletal polarization. 6 However, in the mouse, in vitro and in vivo imaging studies have shown differences in how CTLs and NK cells recognize and eliminate target cells. The signaling cascades controlling the variety of effector functions are perceived to be similar between CTLs and NK cells. 4, 5 In addition to cytotoxicity, another important function of cytotoxic lymphocytes is the production of chemokines and cytokines such as TNF-α and IFN-γ, which promote immunity against intracellular pathogens. Complementing T cell–mediated immunity, NK cells recognize target cells using numerous germline-encoded activation receptors, with such recognition being potentiated by the loss of MHC class I expression on target cells. 3 Accordingly, such CTLs express the CD8 coreceptor for MHC class I. 1, 2 Most perforin-expressing, cytotoxic T lymphocytes (CTLs) recognize target cells using somatically rearranged, clonally distributed TCRs that bind specific MHC class I/peptide complexes on target cells. On release, perforin forms pores in the target cell membrane, facilitating entry of apoptosis-inducing granzymes. Subsets of T cells and natural killer (NK) cells have the capacity to kill pathogen-infected, neoplastic, and certain hematopoietic cells through the targeted release of perforin and granzymes from lytic granules. The present results provide a detailed comparison of human CD3 +CD8 +CD57 bright CTLs and NK cells and suggest that analysis of CD57 bright CTL function may prove useful in the diagnosis of primary immunodeficiencies including familial hemophagocytic lymphohistiocytosis. Therefore, cytotoxic lymphocyte subsets have similar requirements for Munc13-4, syntaxin-11, and Munc18-2 in lytic granule exocytosis. In patients with biallelic mutations in UNC13D, STX11, or STXBP2 associated with familial hemophagocytic lymphohistiocytosis, CTL and NK cell degranulation were similarly impaired. Remarkably, the CTLs produced cytokines more rapidly and with greater frequency than NK cells. On stimulation, such CTLs degranulated more readily than other T-cell subsets, but had a propensity to degranulate that was similar to NK cells. Healthy adult peripheral blood CD3 +CD8 +CD57 bright CTLs expressed more granzyme B but less perforin than CD3 −CD56 dim NK cells. We then compared CD3 +CD8 +CD57 bright CTLs with NK cells. Analysis identified CD57 bright expression as a reliable phenotype of granule marker–containing CTLs. In the present study, we first performed probability-state modeling of differentiation and lytic granule markers on CD8 + T cells to enable the comparison of bona fide CTLs with NK cells. Cytotoxic lymphocytes, encompassing cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, kill pathogen-infected, neoplastic, or certain hematopoietic cells through the release of perforin-containing lytic granules.
0 kommentar(er)
