Mucosal-associated invariant T (MAIT) cell heterogeneity in peripheral blood and bronchoalveolar compartment: implications for TB and HIV immunity.
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Date
2020
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Abstract
Tuberculosis (TB) is the leading cause of infectious mortality globally and the leading cause of death
in people living with human immunodeficiency virus (HIV). Understanding the mechanisms leading
to impaired anti-TB immunity at mucosal sites and how this is altered during HIV infection, may
assist in the development of more effective TB vaccines or immune-based therapies. Mucosalassociated
invariant T (MAIT) cells are depleted and dysfunctional in the peripheral blood during
HIV infection, but little is known about HIV’s impact on their quantity and quality at the lung’s
mucosal surface, the site of TB infection. We aimed to characterise phenotypic, functional and
transcriptomic features of MAIT cells in the peripheral blood and lung mucosa of people with latent
Mycobacterium tuberculosis (Mtb) infection and HIV co-infection.
Matched peripheral blood and bronchoalveolar lavage fluid were collected from consenting
participants with confirmed latent TB infection, either with or without HIV. Characterisation of MHC
class I-related protein 1 (MR1) 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)
tetramer-positive T cells from the lung was performed by cloning, immunophenotyping, functional
assays and T cell receptor sequencing. The phenotype, function and transcriptome of MAIT cells from
both compartments were characterised by surface marker staining, intracellular cytokine staining, as
well as single-cell and bulk RNA-sequencing of MR1 5-OP-RU tetramer-positive T cells from HIVnegative
and HIV-positive individuals.
Peripheral blood MAIT cells were characterised by the CD161++CD26++ phenotype and produced
more interferon (IFN)-γ (P = 0.016) than bronchoalveolar MAIT cells in HIV-negative individuals.
Bronchoalveolar MR1 5-OP-RU tetramer-positive cells, included subpopulations with the atypical
CD161-CD26++ and CD161-CD26- phenotypes. T cell cloning demonstrated that cells from the
typical and atypical CD161/CD26 phenotypic subpopulations all had MR1-restricted function and
MAIT cell consistent T cell receptors. In HIV infection, the frequency of both peripheral blood and
bronchoalveolar MAIT cells was reduced (P = 0.035 and P = 0.047 respectively), with peripheral
blood MAIT cells producing less interleukin (IL)-17 (P = 0.025) and expressing higher levels of the
inhibitory co-stimulatory molecule T cell immunoglobulin and mucin domain-containing protein
(TIM)-3. Interestingly, the phenotype and function of bronchoalveolar MAIT cells remained relatively
unchanged by HIV. Single-cell transcriptional analysis confirmed MAIT cell heterogeneity in the
bronchoalveolar compartment which contained two distinct transcriptional subsets, one associated
with typical MAIT cell features and effector functions and the other associated with alternative MAIT
cell functions including tissue-repair.
We report previously undocumented phenotypic and transcriptional heterogeneity in bronchoalveolar
MAIT cells, which were also less pro-inflammatory than those in peripheral blood. HIV infection led
to depletion of MAIT cells in both compartments, but phenotypic and functional alterations were
more pronounced in the peripheral blood compartment. The preservation of function and
heterogeneity in bronchoalveolar MAIT cells may represent a potential avenue for therapeutic
targeting to restore normal MAIT cell function in people living with HIV. This data suggests that
understanding immune responses requires compartment-specific analyses, which may lead to the
development of more effective vaccines and immunotherapies targeted at inducing immune responses
at the site of infection.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.