Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA‐E during active tuberculosis and express type 2 cytokines

Abstract

CD8 T cells contribute to protective immunity against Mycobacterium tuberculosis. In humans, M. tuberculosis reactive CD8 T cells typically recognize peptides associated to classical MHC class Ia molecules, but little information is available on CD8 T cells recognizing M. tuberculosis Ags presented by nonclassical MHC class Ib molecules.We show here that CD8 T cells from tuberculosis (TB) patients recognize HLA-E-binding M. tuberculosis peptides in a CD3/TCR αβ mediated and CD8-dependent manner, and represent an additional type of effector cells playing a role in immune response to M. tuberculosis during active infection. HLA-E-restricted recognition of M. tuberculosis peptides is detectable by a significant enhanced ex vivo frequency of tetramer-specific circulating CD8 T cells during active TB. These CD8 T cells produce type 2 cytokines upon antigenic in vitro stimulation, help B cells for Ab production, and mediate limited TRAIL-dependent cytolytic and microbicidal activity toward M. tuberculosis infected target cells. Our results, together with the finding that HLA-E/M. tuberculosis peptide specific CD8 T cells are detected in TB patients with or without HIV coinfection, suggest that this is a new human T-cell population that participates in immune response in TB.Keywords: CD8 T lymphocytes r HLA-E r Mycobacterium tuberculosis r TB r Tetramers r Type 2 cytokines Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Francesco Dieli e-mail: francesco.dieli@unipa.it * These authors share first authorship for this work.* * These authors share last authorship for this work. [2]. In humans, M. tuberculosis reactive CD8 T cells recognize peptides associated to classical HLA-A, HLA-B, and HLA-C class I (class Ia) molecules, glycolipids associated to group 1 CD1 molecules [5,6], and mycobacterial Ag associated to MHC class I related molecule (MR1) [7]. However, there is little information on the role that these cells play during infection. In mice, the MHC class Ib molecule H2-M3 binds formylated peptides derived from M. tuberculosis and induces H2-M3-restricted CD8 T cells [8,9] that are protective against M. tuberculosis infection [10]. In humans, CD8 T cells restricted by class Ib molecules comprise the very large majority of the overall M. tuberculosis specific CD8 T-cell response [11] and CD8 T cells recognizing M. tuberculosis Ags in the context of the class Ib molecule HLA-E have been isolated from subjects with latent M. tuberculosis infection [12,13]. However, the functions of this HLA-E-restricted population, as well as its contribution to the host response to M. tuberculosis during infection and disease, remain unknown.HLA-E is the least polymorphic of all the HLA molecules [14] with only two alleles in the Caucasian population, which differ at one aa position located outside the peptidebinding groove [15]. Physiologically, HLA-E binds nonamer peptides derived from the signal sequence of other HLA class I molecules [16,17], a...

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

“…However, stimulating Th1 immunity in TB can also result in excessive inflammation (see Box 1). More recently, the contributions of additional immune pathways have been explored, especially the role of type I interferons (T1-IFNs), Th17 immunity (14, 15), and unconventional T cell immunity (16–18). Little is known about the potential interaction between T1-IFNs and Th17 responses in TB, but interesting observations in this regard have been reported for multiple AID (19–21).…”

Broadly targeted CD8 + T cell responses restricted by major histocompatibility complex E

“…MHC-E-restricted CD8+ T cell responses have been previously identified in human CMV (HCMV), Hepatitis C virus (HCV), Mycobacterium tuberculosis (mTB), and Salmonella enterica infections, typically involving epitopes that are structurally related to the canonical MHC-Ia leader sequence peptides, but foreign to the host (13, 14, 19, 20). To determine the extent to which MHC-E restricts RM CD8+ T cell responses in different settings, we used blocking with high affinity MHC-E-binding peptide VL9 [in conjunction with blocking with anti-MHC-II CLIP peptide and anti-MHC-I monoclonal antibody (mAb) W6/32 (6)] to restriction-classify all SIVgag epitope-specific CD8+ T cell responses in RM vaccinated with strain 68-1 (ΔRh157.5/.4) RhCMV/SIVgag vectors, strain 68-1.2 (Rh157.5/.4-repaired) RhCMV/SIVgag vectors, strain 68-1.2 RhCMV/SIVgag vectors from which the Rh157.5/.4 genes were specifically re-excised (fig.…”

The role of MHC class Ib-restricted T cells during infection

“…HLA-E and Qa-1 bind peptides from bacteria, such as S. typhimurium, S. enterica serovar Typhi, L. monocytogenes , and Mtb (Bouwer et al 1997; Caccamo et al 2015; Lo et al 2000; Salerno-Goncalves et al 2004; van Meijgaarden et al 2015). Interestingly, in the absence of Qdm, a peptide derived from heat shock protein 60 (Hsp60) is primarily loaded into Qa-1 (GMKFDRGYI) (Davies et al 2003).…”

“…This was first proposed when it was determined that the predominant CD8 + T cell response in latently infected patients was MHC class Ia and CD1 independent (Heinzel et al 2002; Lewinsohn et al 2000). The recognition of Mtb --derived peptides presented by HLA-E (Caccamo et al 2015; van Meijgaarden et al 2015) differs from the classically restricted CD8 + T cell response. HLA-E-restricted T cells appear to acquire a Th2 phenotype, producing TNF-α, IL-4, IL-5, IL-10, and IL-13, but have poor cytotoxicity in response to stimulation (Caccamo et al 2015; van Meijgaarden et al 2015).…”

“…The recognition of Mtb --derived peptides presented by HLA-E (Caccamo et al 2015; van Meijgaarden et al 2015) differs from the classically restricted CD8 + T cell response. HLA-E-restricted T cells appear to acquire a Th2 phenotype, producing TNF-α, IL-4, IL-5, IL-10, and IL-13, but have poor cytotoxicity in response to stimulation (Caccamo et al 2015; van Meijgaarden et al 2015). HLA-E and Qa-1 are also capable of presenting virally derived peptides.…”