CD1 antigen presentation and T cell function. In addition to MHC-restricted recognition of peptide antigens, the immune system has evolved the capability to recognize lipid antigens presented by CD1 molecules (Porcelli and Modlin, 1999; Brigl and Brenner, 2004). Humans and mice express CD1d (group 2 CD1); in addition, humans express the group 1 CD1 molecules CD1a, CD1b, and CD1c. Numerous studies have identified diverse infections and a range of non-infectious diseases such as autoimmunity, allergy, and tumor immunity, in which CD1-restricted T cells play critical roles (Brigl and Brenner, 2004; Tupin et al., 2007; Cohen el al., 2009). Our studies are focused on better understanding the roles and functions of CD1-restricted T cells during infection and inflammatory diseases. Harnessing CD1-restricted, lipid-reactive T cells provides intriguing opportunities for the development of novel treatment and vaccine strategies.

Natural Killer T (NKT) cells. Two distinct subsets of CD1d-restricted NKT cells exist in mice and humans, based on their utilization of distinct TCRα and β genes: invariant (iNKT, or type I) and diverse (dNKT, or type II) NKT cells (Bendelac et al., 1997; Godfrey et al., 2004; Brennan, Brigl & Brenner, 2013):

Invariant NKT cells (iNKT, or type I): iNKT cells express an invariant Vα14-Jα18 TCR α-chain, recognize the prototypical α-galactosylceramide (α-GalCer) antigen, and display an activated/memory phenotype in the absence of prior stimulation (Bendelac et al., 1997; Kronenberg, 2005; Brennan, Brigl & Brenner, 2013). Following activation, iNKT cells rapidly produce large amounts of cytokines, followed by cross-activation of other immune cells. Through their interaction with other immune cells, iNKT cells can modulate the evolving innate and adaptive immune responses, but iNKT cells themselves do not generate memory responses. Thus, iNKT cells behave like innate, rather than adaptive lymphocytes. In response to infection or inflammation, iNKT cells can be stimulated either by recognition of microbial lipid antigens, or by an indirect mechanism. The indirect mechanism requires recognition of self-lipid antigens and co-stimulation by inflammatory cytokines secreted by antigen presenting cells in response to microbial products or other inflammatory stimuli (Tupin et al., 2007; Brigl and Brenner, 2010). The indirect mechanism of iNKT cell activation is operational in vivo during a wide range of bacterial and fungal infections (Brigl et al., 2003; Nagarajan et al., 2007; Mattner et al., 2005; Cohen et al., 2011; Brigl et al., 2011), and likely also during non-infectious conditions. Regulation of the expression of potent stimulatory self-lipid antigens plays a critical role in this pathway of iNKT cell activation (Paget et al., 2007; Salio et al., 2007; Brennan et al., 2011). Our focus is to better understanding how the regulation of self-lipid antigen presentation by CD1d as well as soluble mediators and cell-surface ligand/receptor interactions modulate the diverse functions of iNKT cells in protection from and exacerbation of infections and non-infectious inflammatory diseases.

Diverse NKT cells (dNKT, or type II) : In addition to the widely studied Vα14⁺ iNKT cells, CD1d-restricted NKT cells using diverse TCRα and β genes have been described and are commonly referred to as type II or dNKT cells (Godfrey et al., 2004; Rhost et al., 2012; Brennan, Brigl & Brenner, 2013). A number of recent studies have provided important insights into the biology of dNKT cells by demonstrating critical immunomodulatory functions of dNKT cells during infections and non-infectious inflammatory conditions; however, progress in understanding the function of dNKT cells has been significantly impeded by the lack of specific markers to identify dNKT cells and by the limited knowledge of the lipid antigens they recognize. dNKT cells have been identified as a significant population of CD4⁺ T cells remaining in MHC II-deficient mice, in wild-type mice, and in humans, based on their reactivity to CD1d-expressing APCs (Cardell et al., 1995; Behar et al., 1999; Chang et al., 2008). Although dNKT cells use diverse TCRα and β genes, preferential use of certain TCR genes has been reported (Park et al., 2001; Arrenberg et al., 2010).  dNKT cells differ from iNKT cells in other respects. For example, transgenic expression of the TCR of an auto-reactive dNKT hybridoma led to the development of dNKT cells that expressed chemokine receptors and integrins distinct from iNKT cells. dNKT cells do not recognize α-GalCer, and their mode of recognizing sulfatide/CD1d complexes is different from iNKT recognition of lipid/CD1d complexes, and appears more similar to peptide/MHC recognition (Patel et al., 2012; Girardi et al., 2012). Thus, dNKT cells have antigen specificities and functional characteristics distinct from those of iNKT cells. We have recently identified microbial and mammalian phospholipid antigens that are recognized by dNKT cells (Tatituri et al., 2013). Our research is focused on better understanding the antigen specificities and functions of dNKT cells, and to delineate their roles during infection and other non-infectious inflammatory diseases.