Self-Recognition of Cd1 by γ/δ T Cells

Abstract

The specificity of immunoglobulins and α/β T cell receptors (TCRs) provides a framework for the molecular basis of antigen recognition. Yet, evolution has preserved a separate lineage of γ/δ antigen receptors that share characteristics of both immunoglobulins and α/β TCRs but whose antigens remain poorly understood. We now show that T cells of the major tissue γ/δ T cell subset recognize nonpolymorphic CD1c molecules. These T cells proliferated in response to CD1+ presenter cells, lysed CD1c+ targets, and released T helper type 1 (Th1) cytokines. The CD1c-reactive γ/δ T cells were cytotoxic and used both perforin- and Fas-mediated cytotoxicity. Moreover, they produced granulysin, an important antimicrobial protein. Recognition of CD1c was TCR mediated, as recognition was transferred by transfection of the γ/δ TCR. Importantly, all CD1c-reactive γ/δ T cells express Vδ1 TCRs, the TCR expressed by most tissue γ/δ T cells. Recognition by this tissue pool of γ/δ T cells provides the human immune system with the capacity to respond rapidly to nonpolymorphic molecules on professional antigen presenting cells (APCs) in the absence of foreign antigens that may activate or eliminate the APCs. The presence of bactericidal granulysin suggests these cells may directly mediate host defense even before foreign antigen-specific T cells have differentiated.

CD1c molecules broadly survey the endocytic system

“…This predicts holes in the lipid antigen sampling capacity of antigenpresenting cells that do not express both CD1a and -b. Moreover, CD1c molecules seem to present distinct classes of lipid antigens and to be important targets for recognition by the major subset of tissue ␥␦ T cells (4,17). Here, we show that CD1c molecules localize intracellularly in a pattern that is distinct from the other CD1 and MHC class I and class II molecules.…”

“…Further, the fact that the CD8-1 cells recognize and lyse mycobacteria-infected dendritic cells and secrete granulysin that can directly kill released mycobacteria (3,5) makes it likely that CD1c may mediate effective anti-mycobacteria immune responses at an early phase of infection. In addition, we recently found that the major tissue subset of granulysin-containing cytolytic ␥␦ T cells recognize CD1c (17). Together, these features of its broad sampling within the endocytic system, presentation of distinct subclasses of lipid antigens, and expression alone or along with other CD1 isoforms offer the immune system a valuable opportunity to sample the universe of lipid antigens and activate effector ␣␤ and ␥␦ T cells.…”

Binding ofEscherichia coliadhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA

“…Ligands of these molecules have been defined. Human CD1c is recognized directly by V␦1ϩ T cells in the absence of antigen (35), and CD1d presents the glycolipid ␣-galactosylceramide to NK T cells (36) as shown by tetramer staining (37). Despite the lack of MICA͞B homologs in rodents, two murine NKG2D ligands, H-60 and Rae 1b, have been described (38,39).…”

Plasmodium falciparum Infection of Human Volunteers Activates Monocytes and CD16 + Dendritic Cells and Induces Upregulation of CD16 and CD1c Expression

“…It is further unknown which glycophospholipids of the malaria parasite or human erythrocytes are presented by CD1c. However, a subset of ␥␦T cells has been identified that recognizes CD1c independently of foreign lipid or glycolipid antigens (30). Therefore, parasite-induced upregulation of CD1c (presenting self-lipids) might be sufficient to activate ␥␦T cells without the need for malaria antigen processing and presentation, circumventing potential inhibition of this presentation.…”

“…Therefore, parasite-induced upregulation of CD1c (presenting self-lipids) might be sufficient to activate ␥␦T cells without the need for malaria antigen processing and presentation, circumventing potential inhibition of this presentation. The early upregulation of CD1c expression might be specifically responsible for initiating the cascade of the early activation and expansion of the ␥␦T-cell compartment and therefore the early production of gamma interferon (IFN-␥) (19), leading to further activation of ␣␤T cells (30) and the induction of memory responses.…”