Identification of novel Mycobacterium tuberculosis CD4 T-cell antigens via high throughput proteome screening - 09/05/15

Doi : 10.1016/j.tube.2015.03.001

Kaustuv Nayak ^a,^{^{1
Contributed equally as first authors.}} , Lichen Jing ^b,^{^{1
Contributed equally as first authors.}} , Ronnie M. Russell ^b , D. Huw Davies ^c,^d , Gary Hermanson ^d , Douglas M. Molina ^d , Xiaowu Liang ^d , David R. Sherman ^e,^f , William W. Kwok ^g , Junbao Yang ^g , John Kenneth ^h , Syed F. Ahamed ^h , Anmol Chandele ^a,ⁱ , Kaja Murali-Krishna ^a,^i,^j,^{^{2
Contributed equally as senior authors.}} , David M. Koelle ^b,^f,^g,^k,^l,^⁎,^{^{2
Contributed equally as senior authors.}}
^a ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
^b Department of Medicine, Division of Infectious Diseases, University of Washington, Box 358061, Seattle, WA 98195, USA
^c Department of Medicine, Division of Infectious Diseases, University of California, Room 376D Med-Surg II, Irvine, CA 92697-4068, USA
^d Antigen Discovery, Inc., 1 Technology Drive Suite E309, Irvine, CA 92618, USA
^e Seattle Biomedical Research Institute, 307 Westlake Ave. North, No. 500, Seattle, WA 98109, USA
^f Department of Global Health, University of Washington, Box 359931, Seattle, WA 98195, USA
^g Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA, 98101, USA
^h Division of Infectious Diseases, St. John's Research Institute, St. John's National Academy of Health Sciences, Sarjapur Road, Koramangala 2 Block, Bangaluru, Karnataka 560034, India
ⁱ Emory Vaccine Center, 1510 Clifton Road, Atlanta, GA 30329, USA
^j Department of Pediatrics, Emory University, 1760 Haygood Drive, Atlanta, GA 30322, USA
^k Department of Laboratory Medicine, University of Washington, Box 358070, Seattle, WA 98195, USA
^l Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, 1100 Eastlake Ave. East, Seattle, WA 98109, USA

^∗Corresponding author. University of Washington, 750 Republican Street, Room E651, Seattle, WA 98109, USA. Tel.: +1 206 616 1940; fax: +1 206 616 4984.

Summary

Elicitation of CD4 IFN-gamma T cell responses to Mycobacterium tuberculosis (MTB) is a rational vaccine strategy to prevent clinical tuberculosis. Diagnosis of MTB infection is based on T-cell immune memory to MTB antigens. The MTB proteome contains over four thousand open reading frames (ORFs). We conducted a pilot antigen identification study using 164 MTB proteins and MTB-specific T-cells expanded in vitro from 12 persons with latent MTB infection. Enrichment of MTB-reactive T-cells from PBMC used cell sorting or an alternate system compatible with limited resources. MTB proteins were used as single antigens or combinatorial matrices in proliferation and cytokine secretion readouts. Overall, our study found that 44 MTB proteins were antigenic, including 27 not previously characterized as CD4 T-cell antigens. Antigen truncation, peptide, NTM homology, and HLA class II tetramer studies confirmed malate synthase G (encoded by gene Rv1837) as a CD4 T-cell antigen. This simple, scalable system has potential utility for the identification of candidate MTB vaccine and biomarker antigens.

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Keywords : Tuberculosis, CD4, T-cell, Antigen, CD137, Malate synthase, Tetramer

Abbreviations : MTB, ORF, IVTT, ATBI, LTBI, TST, PPD, IGRA, ICC, IFN-gamma, IL-2, PBMC, CFSE, TCR, PCR, RTS, DMSO, CFP, ESAT, PHA, PBMC, SEB, IB, mAb, TCM, MCB, SDS, PE, EBV, LCL

Plan

Introduction

Materials and methods

Subjects and specimens

Expansion of MT-reactive cell populations from PBMC

Subjects and specimens

Enrichment of MTB-specific CD4 T-cells

Screen of the partial MTB proteome

ORFeome screens in a resource- and cell-limited setting

Confirmation of positive CD4 T cell responses and evaluation of cross-reactivity

Characteristics of the MTB proteins eliciting CD4 T-cell responses

Discussion

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Vol 95 - N° 3

P. 275-287 - mai 2015 Retour au numéro

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Identification of novel Mycobacterium tuberculosis CD4 T-cell antigens via high throughput proteome screening - 09/05/15

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