HLA-E–dependent Presentation of Mtb-derived Antigen to Human CD8+ T Cells

Abstract

Previous studies in mice and humans have suggested an important role for CD8+ T cells in host defense to Mtb. Recently, we have described human, Mtb-specific CD8+ cells that are neither HLA-A, B, or C nor group 1 CD1 restricted, and have found that these cells comprise the dominant CD8+ T cell response in latently infected individuals. In this report, three independent methods are used to demonstrate the ability of these cells to recognize Mtb-derived antigen in the context of the monomorphic HLA-E molecule. This is the first demonstration of the ability of HLA-E to present pathogen-derived antigen. Further definition of the HLA-E specific response may aid development of an effective vaccine against tuberculosis.

Identification of a Human HLA-E-Restricted CD8+ T Cell Subset in Volunteers Immunized withSalmonella entericaSerovar Typhi Strain Ty21a Typhoid Vaccine

“…3). Even though the possibility that the anti-HLA-E mAbs used in our studies were weak blockers cannot be ruled out, our results are supported by those reported by Heinzel et al (18), who, in unpublished data, found that mAb to pan-HLA I (clone W6/32) were capable of inhibiting CD8 ϩ T cell-dependent recognition in an HLA-E-restricted system. Unfortunately, the frequencies of effectors that release granzyme B to S. Typhi-infected autologous blasts or S. Typhi-infected 721.221.AEH cannot be directly compared because of the differential expression of HLA-E between these cells (i.e., 721.221.AEH cells express considerably higher numbers of HLA-E molecules than blasts; Fig.…”

“…The HLA class I-defective B cell line 721.221 as well its transfectants 721.221.AEH (which has been transfected with HLA-E fused to the HLA-A2 leader peptide, and therefore express the HLA-E*0101 allele on the cell surface), 721.221.F (which was transfected only with HLA-F), and 721.221.E6 (which was transfected with HLA-E without a leader peptide) were provided by Dr. D. Geraghty (14,18). The 721.221 cell line is characterized by the lack of expression of HLA-class Ia A, B, and C due to gamma ray-induced mutation in the HLA complex.…”

“…(12), and 2) the W6/32 mAb blocks both classical and nonclassical HLA class I molecules such as HLA-E (37), we explored the possibility that HLA-E molecules might play a role in mediating the CTL activity observed in Ty21a vaccinees. To this end, CTL were assayed for their ability to kill the S. Typhi-infected B lymphoblastoid cell line 721.221 (a cell line characterized by the lack of expression of HLA-A, -B, -C, or -G, which does not normally exhibit HLA-E at the surface (11), as well as its transfectants expressing in the cell membrane HLA-E (721.221.AEH) or HLA-F (721.221.F) (14,18). Cells transfected with HLA-E that is expressed only intracellularly (E6) were also used as controls in these experiments.…”

“…The anti-HLA-E mAb was provided by Dr. D. Geraghty (3D12 clone; Fred Hutchinson Cancer Research Center, Seattle, WA) (14,18) or purchased from Abcam (MEM-E/06 and MEM-E/02 clones; Cambridge, MA) (29). Anti-CD1 mAbs were obtained from commercial sources: antiCD1a (clone NA1/34) from Serotec (Oxford, U.K.), anti-CD1b (clone WM25) from Research Diagnostics (Flanders, NJ), and anti-CD1c (clone L161) from Serotec.…”

“…Moreover, HLA-E expression has been detected in several nonlymphoid tissues, including liver, skin, lung, and, notably, placental cells (16). HLA-E molecules have been shown to interact with two cell subsets: NK cells (11) by CD94/ NKG2A, -B, and -C receptors (17) and, in a single report in humans infected with Mycobacterium tuberculosis, a subpopulation of CD8 ϩ T cells (18) by an unknown receptor. In this study we investigated the mechanisms involved in killing of S. Typhi-infected targets by specific-CD8 ϩ T cells using cells obtained from volunteers immunized with Ty21a as a prototype of live attenuated typhoid vaccine.…”