Human CD8 ⁺ T-cells Recognizing Peptides from Mycobacterium tuberculosis ( Mtb) Presented by HLA-E Have an Unorthodox Th2-like, Multifunctional, Mtb Inhibitory Phenotype and Represent a Novel Human T-cell Subset

Abstract

Mycobacterial antigens are not exclusively presented to T-cells by classical HLA-class Ia and HLA-class II molecules, but also through alternative antigen presentation molecules such as CD1a/b/c, MR1 and HLA-E. We recently described mycobacterial peptides that are presented in HLA-E and recognized by CD8 ⁺ T-cells. Using T-cell cloning, phenotyping, microbiological, functional and RNA-expression analyses, we report here that these T-cells can exert cytolytic or suppressive functions, inhibit mycobacterial growth, yet express GATA3, produce Th2 cytokines (IL-4,-5,-10,-13) and activate B-cells via IL-4. In TB patients, Mtb specific cells were detectable by peptide-HLA-E tetramers, and IL-4 and IL-13 were produced following peptide stimulation. These results identify a novel human T-cell subset with an unorthodox, multifunctional Th2 like phenotype and cytolytic or regulatory capacities, which is involved in the human immune response to mycobacteria and demonstrable in active TB patients’ blood. The results challenge the current dogma that only Th1 cells are able to inhibit Mtb growth and clearly show that Th2 like cells can strongly inhibit outgrowth of Mtb from human macrophages. These insights significantly expand our understanding of the immune response in infectious disease.

Author Summary

Pathogens like Mycobacterium tuberculosis (Mtb) are recognized by human T-cells following their presentation in HLA molecules. HLA class I molecules can be divided into two types, classical as well as non-classical HLA molecules. Here we studied the non-classical HLA family member, HLA-E, which displays only minimal genetic variation between individuals and is relative resistant to down modulation by HIV infection. We have characterized the T-cells that recognize Mtb in the context of HLA-E in detail and found that these human CD8 ⁺ T-cells had unexpected, unorthodox properties: in contrast to most classical CD8 ⁺ T-cells, the T-cells activated by HLA-E uniquely produced Th2 (IL-4, IL-5, IL-13) instead of the usual Th1 cytokines, and were able to activate B-cells and induced cytokine production by these B-cells. Moreover, these HLA-E restricted CD8 ⁺ T-cells inhibited Mtb growth inside cells, an important property to contribute to resolution of the infection. Thus these T-cells represent a new player in the human immune response to infection, and add B-cell activation to the key pathways following infection with Mtb.