What Role Does the Route of Immunization Play in the Generation of Protective Immunity against Mucosal Pathogens? This information is current as Igor M. Belyakov and Jeffrey D. Ahlers of October 3, 2021. J Immunol 2009; 183:6883-6892; ; doi: 10.4049/jimmunol.0901466 http://www.jimmunol.org/content/183/11/6883 Downloaded from References This article cites 92 articles, 38 of which you can access for free at: http://www.jimmunol.org/content/183/11/6883.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 3, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. What Role Does the Route of Immunization Play in the Generation of Protective Immunity against Mucosal Pathogens? Igor M. Belyakov1* and Jeffrey D. Ahlers† The route of vaccination is important in influencing im- stream, although some microorganisms are limited to the de- mune responses at the initial site of pathogen invasion velopment of disease only at the site of initial mucosal invasion where protection is most effective. Immune responses (8, 13, 14). For HIV, numerous studies have demonstrated that required for mucosal protection can differ vastly de- the gut mucosa is the predominant site of viral replication and pending on the individual pathogen. For some mucosal amplification (15). pathogens, including acute self-limiting infections, Protective immunity against mucosal pathogens will require Downloaded from high-titer neutralizing Abs that enter tissue parenchyma novel vaccine strategies to induce mucosal immune responses or transude into the mucosal lumen are sufficient for tailored to the anatomic location and the threat of the invading pathogen (16–32). However, the requirement for mucosal im- clearing cell-free virus. However, for pathogens causing munization to generate protective “frontline immunity” against chronic infections such as HIV, hepatitis C virus, herpes mucosal pathogens is highly controversial. On the one hand, viruses, mycobacteria, and fungal and parasitic infec- numerous studies in the literature have demonstrated that im- http://www.jimmunol.org/ tions, a single arm of the immune response generated by mune responses are readily detectable at mucosal sites following systemic vaccination may be insufficient for protection. systemic delivery of vaccines, and complete or partial protection Induction of the mucosal innate and adaptive immune -؉ from mucosal challenge is attainable (2, 33–40). Systemic im systems, including CD4 T help, Th17, high avidity ؉ munization is adequate for successful vaccines for some mucosal CD8 CTL, and secretory IgA and IgG1 neutralizing pathogens, notably the polio virus and the influenza virus, Abs, at the site of pathogen entry may be required for where high titers of neutralizing Abs are capable of clearing cell- effective protection against highly invasive pathogens free virus and preventing disease (34, 41). On the other hand, that lead to chronic infection and may be generated pre- mucosal pathogens such as HIV-1, HPV, herpes viruses, Myco- by guest on October 3, 2021 dominantly by mucosal vaccination. The Journal of bacterium species, and other intracellular pathogens may re- Immunology, 2009, 183: 6883–6892. quire mucosal vaccine strategies that activate multiple arms of the innate and adaptive immune systems (29, 30, 42–45). We as well as others have shown that protective mucosal immune he major entry point for many human pathogens oc- responses are most effectively induced by mucosal immuniza- curs at gastrointestinal (e.g., polio virus, Escherichia tion through oral, intranasal (i.n.), intrarectal, or intravaginal T coli, Salmonella, Shigella, Vibrio cholerae, Helicobacter routes, and an optimized mucosal vaccination strategy may pylori, and HIV-1), respiratory (e.g., influenza virus, Mycobac- have a much greater potential for generating local protective terium tuberculosis, adenovirus, coronavirus, rhinovirus, respi- mucosal immune responses (30, 46–52). Studies evaluating ratory syncytial virus), or genital (HSV, human papillomavirus mucosal infection and immunization in humans and animals (HPV),2 HIV-1, Chlamydia, and Neisseria gonorrhoeae) muco- have demonstrated the existence of a common mucosal im- sal surfaces (1–11). The main function of the innate mucosal mune system (CMIS) that consists of gastrointestinal, respira- immune system, to discriminate between dangerous and innoc- tory, and genital mucosa (3, 46, 53, 54). The CMIS implies the uous organisms, is determined by the recognition of specific ability of Ag-specific lymphocytes to home to mucosal effector pathogen-associated molecular patterns via activation of TLRs, sites in addition to the site where initial Ag exposure occurred NOD-like receptors, retinoic acid (RA)-inducible gene I-like (53). Different mucosal routes of immunization such as oral, helicases, and C-type lectins (12). Mucosal pathogens may dis- nasal, or rectal routes can induce generalized mucosal immune seminate to distant systemic sites through entry into the blood responses not only at the portals of entry of infectious agents but *Midwest Research Institute, Frederick, MD 21702; and †National Institute of Allergy and 2 Abbreviations used in this paper: HPV, human papillomavirus; ASC, Ab-secreting cell; Infectious Diseases, National Institutes of Health, Bethesda, MD 20817 BCG, bacillus Calmette-Gue´rin; CMIR, compartmentalized mucosal immune response; CMIS, common mucosal immune system; DC, dendritic cell; i.n., intranasal; IPV, inactive Received for publication September 9, 2009. Accepted for publication October 14, 2009. poliovirus vaccine; iTreg, induced Treg; LP, lamina propria; MLN, mesenteric lymph The costs of publication of this article were defrayed in part by the payment of page charges. node; OPV, oral poliovirus vaccine; RA, retinoic acid; SHIV, simian/human immunode- This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. ficiency virus; sIg, secretory Ig; TB, tuberculosis; Treg, regulatory T cell; VLP, virus-like Section 1734 solely to indicate this fact. particle. 1 Address correspondence and reprint requests to Prof. Igor M. Belyakov, Midwest Re- search Institute, 110 Thomas Johnson Drive, Frederick, MD 21702. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901466 6884 BRIEF REVIEWS: COMPARTMENTALIZED MUCOSAL IMMUNE RESPONSE AND PROTECTION Downloaded from FIGURE 1. Schema of compartmentalized immunity (functional CD8ϩ CTL activity and avidity and neutralizing IgG and sIgA antibodies) according to the site http://www.jimmunol.org/ of immunization. CMIR contributes to the protection of macaques against SIV depletion of mucosal CD4ϩ T cell after optimum mucosal vaccination (46). CTL that can recognize peptide/MHC only at high Ag density are termed low avidity CTLs, whereas those that can recognize their cognate Ag at low densities are termed high avidity CTLs (93). High avidity CTLs are essential for the effective clearance of viral infections and for the elimination of tumors. The high avidity CD8ϩ T cells are predominately found compartmentalized at the site of vaccination. The simple application of the Ag on a mucosal surface does not guarantee the success of mucosal vaccination. Non-optimal mucosal vaccination (upper panel) may provide limited mucosal immunity (both functional CD8ϩ CTL and neutralizing anti- bodies) and limited protection against mucosal challenge. Optimal mucosal immunization (lower panel) depends on multiple factors including type of Ag, targeting and delivery of Ag to Dcs, mucosal adjuvant, and frequency of immunization. Optimal mucosal vaccination is most effective in the generation of mucosal immunity (natural antibodies (NAb) IgG and IgA, high-avidity CD8ϩ CTL, and CD4ϩ T cells) and complete protection against mucosal infection. Systemic immunization is less effective in generation of high-avidity CTL and NAb at mucosal sites and may result in only partial protection from mucosal challenge. Green arrows indicate by guest on October 3, 2021 cell migration toward mucosal tissue and the red arrows indicate cell migration to systemic lymphoid tissue. Thick arrows indicate a higher frequency of functionally active Ag-specific T and B cells in the tissue proximal to the site of vaccination, whereas the thin arrows indicate limited immune responses at the distant sites. ϩ in distant mucosal effector sites as well, although additional tor/memory CD8 cells in mucosal effector sites (lamina pro- constraints on mucosal compartmentalization are evidently de- pria (LP)) will be crucial in containing initial viral replication pendent upon the adjuvant and the Ag delivery vehicle. The and subsequent disease course following HIV infection. Induc- ϩ term mucosal compartmentalization