Invariant Natural Killer (iNK)T cells play opposite immune functions. They participate in the innate immune response to promote anti-microbial and anti-tumor immunity and they are crucial to maintain T cell tolerance and prevent autoimmune diseases. While it is well known that the adjuvant function of iNKT cells is mediated through maturation of dendritic cells (DC), the mechanism underlying the tolerogenic function of iNKT cells remains unclear. We performed co-culture experiments with immature myeloid DC and purified regulatory iNKT cells and found that under steady-state conditions, i.e. in the absence of any other maturation signal, iNKT cells triggered a unique pathway of DC maturation. iNKT cell-modulated DC (nkt-DC) showed the phenotype of tolerogenic mature DC with intermediate levels of expression of MHC class II and co-stimulatory molecules and a predominant secretion of the modulatory cytokine IL-10 with minimal release of pro-inflammatory cytokines (IL-12 and IL-6). Our experiments in transwells, with blocking anti-cytokine mAbs and with knockout DC lacking key molecules involved in the DC-(iNK)T cell interaction (CD1d, ICAM-1, CD40) showed that the iNKT cell-modulation of DC required cell-cell contact while cytokine were dispensable. Together with the phenotypical markers of tolerogenic DC, nkt-DC showed important tolerogenic function both in vitro and in vivo. Specifically, they were able to induce antigen-specific regulatory T cells from naïve diabetogenic BDC2.5 CD4 T cells (characterized by an anergic state, strong immunosuppressive capacity and secretion of immunomodulatory cytokines like IL-10) both in vitro and in vivo and to protect toward the development of an autoimmune disease (like T1D in NOD mouse). On the contrary, in the presence of pathogens (such as LPS) NKT cells exert an adjuvant effect and sustain the proinflammatory DC maturation (up-regulation of the maturation markers and increased IL12p70 production) favoring, in this way, the clearance of the pathogens. Our data suggest that, depending on the environment in which the two cells populations are present, NKT cells might exert a tolerogenic or an immunogenic role by affecting directly DCs maturation.

(2009). On/off TLR segnaling decides immunogenic or tolerogenic dendritic cell maturation upon NKT cell contact. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2009).

On/off TLR segnaling decides immunogenic or tolerogenic dendritic cell maturation upon NKT cell contact

CAIELLI, SIMONE
2009

Abstract

Invariant Natural Killer (iNK)T cells play opposite immune functions. They participate in the innate immune response to promote anti-microbial and anti-tumor immunity and they are crucial to maintain T cell tolerance and prevent autoimmune diseases. While it is well known that the adjuvant function of iNKT cells is mediated through maturation of dendritic cells (DC), the mechanism underlying the tolerogenic function of iNKT cells remains unclear. We performed co-culture experiments with immature myeloid DC and purified regulatory iNKT cells and found that under steady-state conditions, i.e. in the absence of any other maturation signal, iNKT cells triggered a unique pathway of DC maturation. iNKT cell-modulated DC (nkt-DC) showed the phenotype of tolerogenic mature DC with intermediate levels of expression of MHC class II and co-stimulatory molecules and a predominant secretion of the modulatory cytokine IL-10 with minimal release of pro-inflammatory cytokines (IL-12 and IL-6). Our experiments in transwells, with blocking anti-cytokine mAbs and with knockout DC lacking key molecules involved in the DC-(iNK)T cell interaction (CD1d, ICAM-1, CD40) showed that the iNKT cell-modulation of DC required cell-cell contact while cytokine were dispensable. Together with the phenotypical markers of tolerogenic DC, nkt-DC showed important tolerogenic function both in vitro and in vivo. Specifically, they were able to induce antigen-specific regulatory T cells from naïve diabetogenic BDC2.5 CD4 T cells (characterized by an anergic state, strong immunosuppressive capacity and secretion of immunomodulatory cytokines like IL-10) both in vitro and in vivo and to protect toward the development of an autoimmune disease (like T1D in NOD mouse). On the contrary, in the presence of pathogens (such as LPS) NKT cells exert an adjuvant effect and sustain the proinflammatory DC maturation (up-regulation of the maturation markers and increased IL12p70 production) favoring, in this way, the clearance of the pathogens. Our data suggest that, depending on the environment in which the two cells populations are present, NKT cells might exert a tolerogenic or an immunogenic role by affecting directly DCs maturation.
BIONDI, ANDREA
FALCONE, MARIKA
dentric, NKT cells, regulatory T cells, tolerance
BIO/13 - BIOLOGIA APPLICATA
English
MEDICINA TRASLAZIONALE E MOLECOLARE (DIMET) - 45R
22
2008/2009
(2009). On/off TLR segnaling decides immunogenic or tolerogenic dendritic cell maturation upon NKT cell contact. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2009).
File in questo prodotto:
File Dimensione Formato  
phd_unimb_708295.pdf

embargo fino al 26/11/2012

Tipologia di allegato: Doctoral thesis
Dimensione 2.25 MB
Formato Adobe PDF
2.25 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/7544
Citazioni
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
Social impact