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T Cells Take on Zika Virus

2017; Cell Press; Volume: 46; Issue: 1 Linguagem: Inglês

10.1016/j.immuni.2016.12.020

1097-4180

Heather D. Hickman, Theodore C. Pierson,

Virology and Viral Diseases

Although CD8+ T cells provide protection against many viral infections, their role in Zika virus (ZIKV) immunity has not been extensively examined. In a recent issue of Cell Host & Microbe, Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar define antigenic epitopes determining CD8+ T cell immunity in murine models of ZIKV infection. Although CD8+ T cells provide protection against many viral infections, their role in Zika virus (ZIKV) immunity has not been extensively examined. In a recent issue of Cell Host & Microbe, Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar define antigenic epitopes determining CD8+ T cell immunity in murine models of ZIKV infection. Zika virus (ZIKV) is a mosquito-born, positive-stranded RNA virus that has skyrocketed into public awareness due to its rapid dissemination among countries of the Western hemisphere. Although ZIKV infection of adults is generally asymptomatic and self-limiting, infection during pregnancy can lead to severe neurodevelopmental birth defects in utero including microcephaly (Hazin et al., 2016Hazin A.N. Poretti A. Turchi Martelli C.M. Huisman T.A. Di Cavalcanti Souza Cruz D. Tenorio M. van der Linden A. Pena L.J. Brito C. Gil L.H. et al.Microcephaly Epidemic Research GroupN. Engl. J. Med. 2016; 374: 2193-2195Crossref PubMed Scopus (189) Google Scholar). Identifying unique features of ZIKV pathogenesis and strategies to prevent new infections has become a public health priority. Efforts to develop ZIKV vaccines that elicit protective, neutralizing antibodies (Abs) combined with theoretical concerns about the potential enhancement of ZIKV infection by antibodies that cross-react with other flaviviruses, such as dengue virus (DENV), has driven intense examination of the humoral response to ZIKV in both humans and animal models. In contrast, to date, relatively little is known regarding the CD8+ T cell response to ZIKV infection. In a recent issue of Cell Host & Microbe, Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar map the antigenic epitopes that elicit murine CD8+ T cell responses during ZIKV infection and demonstrate a protective role for these cells during infection. In contrast to antibodies that bind to virions before they enter cells, CD8+ T cells recognize and eliminate virus-infected cells after recognition of short peptides bound by major histocompatibility class I (MHC) molecules. A multitude of factors influence which specific CD8+ T cells will respond during a viral infection, including but not limited to peptide creation, MHC allelic polymorphism (dictating the peptide repertoire), T cell precursor frequencies, and T cell immunodominance. How these factors act in concert is incompletely understood. Although cytotoxic CD8+ T cells have been shown to play a protective role against DENV and West Nile virus (WNV) (Screaton et al., 2015Screaton G. Mongkolsapaya J. Yacoub S. Roberts C. Nat. Rev. Immunol. 2015; 15: 745-759Crossref PubMed Scopus (235) Google Scholar, Shrestha and Diamond, 2004Shrestha B. Diamond M.S. J. Virol. 2004; 78: 8312-8321Crossref PubMed Scopus (322) Google Scholar, Weiskopf and Sette, 2014Weiskopf D. Sette A. Front. Immunol. 2014; 5: 93Crossref PubMed Scopus (108) Google Scholar), their contribution to ZIKV immunity has not been examined. To begin to define the CD8+ response to ZIKV, Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar used peptide-binding prediction algorithms to identify peptides encoded by two strains of ZIKV (MR766 and FSS13025) that could be bound by the MHC class I molecules Kb and Db in the commonly used C57BL/6 mouse. These algorithms identified 244 potential ZIKV-derived peptides; 202 of these were shared between the African- and Asian-lineage ZIKV strains studied. To identify which, if any, of these peptides elicited CD8+ T cell responses, Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar examined the CD8+ response in two murine models of ZIKV infection. ZIKV replicates poorly in wild-type mouse strains due to an inability to efficiently antagonize the type I interferon response (Lazear et al., 2016Lazear H.M. Govero J. Smith A.M. Platt D.J. Fernandez E. Miner J.J. Diamond M.S. Cell Host Microbe. 2016; 19: 720-730Abstract Full Text Full Text PDF PubMed Scopus (675) Google Scholar). After infection of mice treated with interferon α/β receptor (IFNAR)-blocking Ab, isolated splenic CD8+ T cells produced IFN-γ when stimulated with 26 different peptides from MR766 and 15 peptides from FSS13025 ZIKV strains. To confirm these findings in a more immunocompetent model, Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar used H-2Kb mice that lack IFNAR in only a subset of myeloid cells. In these LysMCre+IFNARfl/fl mice, IFN signaling remains intact in T cells, B cells, and dendritic cells (DCs). CD8+ T cells isolated from ZIKV-infected LysMCre+IFNARfl/fl animals responded to the same ZIKV epitopes as CD8+ T cells isolated from mice treated with IFNAR-blocking antibody. Although CD8+ T cell epitopes were identified from almost all of ZIKV's ten proteins, the response to envelope (E protein)-derived epitopes predominated in both murine models (Figure 1). Interestingly, CD8+ T cells in C57BL/6 mice infected with DENV also possess T cells targeting the structural proteins capsid (C) and E (Yauch et al., 2009Yauch L.E. Zellweger R.M. Kotturi M.F. Qutubuddin A. Sidney J. Peters B. Prestwood T.R. Sette A. Shresta S. J. Immunol. 2009; 182: 4865-4873Crossref PubMed Scopus (272) Google Scholar). In contrast, DENV-specific human T cells or T cells from DENV-infected HLA-transgenic mice (possessing human MHC alleles) are focused predominantly on nonstructural proteins (Weiskopf and Sette, 2014Weiskopf D. Sette A. Front. Immunol. 2014; 5: 93Crossref PubMed Scopus (108) Google Scholar). Whether CD8+ T cell targeting of structural proteins is a unique feature of presentation by murine class I molecules or of ZIKV (compared to DENV) infection remains to be determined. What is the function of ZIKV-specific T cells elicited by infection? Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar show that depletion of CD8+ T cells resulted in higher viral titers after infection with either strain of virus. Likewise, the transfer of memory CD8+ T cells into naive LysMCre+IFNARfl/fl mice that were subsequently infected reduced viral burden. Finally, the authors examined infection of wild-type or CD8α-deficient mice with the mouse-adapted African ZIKV strain Dakar 41519. While Cd8a−/− mice uniformly succumbed to infection, only 25% of wild-type mice died. Thus, using three complementary approaches, Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar demonstrate that CD8+ T cells afford considerable protection during ZIKV infection. While the findings of Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar add to our understanding of the CD8+ T cell response to ZIKV, it is important to note a limitation of their approach. Peptide-binding prediction algorithms might miss any peptide created in an unexpected manner, such as longer peptides or those that bind with non-canonical anchor residues. Additionally, increasing numbers of peptides are being identified from non-predicted protein sources, such as the products of alternative reading frames, untranslated regions, or translation initiation at non-AUG codons (Starck and Shastri, 2016Starck S.R. Shastri N. Immunol. Rev. 2016; 272: 8-16Crossref PubMed Scopus (40) Google Scholar). Many of these "cryptic peptides" are being discovered via direct mass spectrometric sequencing after peptide elution from MHC molecules (Laumont et al., 2016Laumont C.M. Daouda T. Laverdure J.P. Bonneil É. Caron-Lizotte O. Hardy M.P. Granados D.P. Durette C. Lemieux S. Thibault P. Perreault C. Nat. Commun. 2016; 7: 10238Crossref PubMed Scopus (133) Google Scholar). There is also a practical upside to characterization of non-standard viral peptides—discovery of novel viral proteins that encode these peptides. With more analyses, is likely that other CD8+ epitopes relevant to ZIKV immunity await discovery. It will be important to extend these studies to the identification of HLA-binding peptides for common human alleles, which will differ from those peptides that have been identified here and may even derive from different ZIKV proteins than those in mice. Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Cell Host Microbe. 2017; 21 (Published online January 11, 2017)Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar present a framework for the examination of ZIKV-specific T cells in murine models with considerable utility for vaccine development. Antibodies are a correlate of protection after vaccination with most licensed flavivirus vaccines (e.g., yellow fever virus). While vaccine-mediated protection from peripheral ZIKV viremia can be conferred by the Ab transfer in mice and non-human primates, ZIKV vaccine candidates do elicit T cell responses (Abbink et al., 2016Abbink P. Larocca R.A. De La Barrera R.A. Bricault C.A. Moseley E.T. Boyd M. Kirilova M. Li Z. Ng'ang'a D. Nanayakkara O. et al.Science. 2016; 353: 1129-1132Crossref PubMed Scopus (389) Google Scholar). As the immune response required to protect the fetus after maternal challenge remains unknown, a more complete understanding of the repertoire of T cells responding to ZIKV and their contribution to protection in preclinical murine models of ZIKV infection or vaccination may be important. Thus, detailed studies of the T cell response in mice and ultimately humans will provide a more complete picture of immunity to a flavivirus with an unusual pathogenesis.