Generation of both cross-reactive and virus-specific T-cell populations after immunization with serologically distinct influenza A viruses.

Effros, Rita B.; Doherty, Peter C.; Gerhard, Walter; Bennink, Jack R.

doi:10.1084/jem.145.3.557

Cited by 269 publications

(179 citation statements)

References 24 publications

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“…§ As in Table L influenza A/JAP/57 hemagglutinin induced a CTL response in vitro from spleen cells previously primed to A/JAP/57 virus ( Table I). As has been demonstrated (16,23,24), the CTL response to stimulator cells infected with a given type A influenza virus is characterized by a high degree of cross-reactivity for target cells infected with type A virus of any subtype. This response is mediated by a discrete subpopulation of cross-reactive CTLs (16,24).…”

Section: Gtntral Male Balb/c (H-2d) and Cba/h (H-mentioning

confidence: 88%

Specificity of cytotoxicity T cells directed to influenza virus hemagglutinin.

Braciale¹

1979

The Journal of Experimental Medicine

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Because the initial realization that T cells comprised a discrete lymphocyte class, there has been a great deal of experimental work directed toward an analysis of the nature of the antigen receptor on T cells and, concomitantly, toward an assessment of the comparative specificity of T and B cells. Perhaps a major advance in understanding the molecular nature of the antigen receptor on T cells has come from studies demonstrating the expression, on the surface of specific T cells, of idiotypie determinants (immunoglobulin heavy chain variable region gene products [Vn]) 1 which are shared with the corresponding antibody (1-3). Although from such observations it might be anticipated that T cells and antibody would have comparable degrees of specificity for antigen, analyses of T-cell specificity have not necessarily fulfilled this expectation (reviewed in reference 4).A major limitation in many analyses of T-cell specificity has been the need to rely on ancillary T-cell activities, i.e., the capacity of T cells to help or suppress humoral responses or exhibit delayed-type hypersensitivity manifestations in order to assess Tcell recognition of antigen. This limitation would appear to be less severe in the case ofcytotoxic T lymphocyte (CTL) responses as antigen recognition by CTLs is directly measured by their capacity to lyse target cells expressing the appropriate antigen (5). Thus an analysis of the fine specificity of CTL recognition could provide useful information on the comparative specificities of T and B cells.Studies on the CTL response to conventional (i.e., non major histocompatibility complex [MHC] encoded) antigen have already yielded some information with regard to CTL specificity. For example, virus-specific CTLs readily distinguish target cells infected with unrelated viruses (6). Furthermore, more recent evidence along these lines suggests that distinct viral antigens are specifically recognized by CTLs (7-1 1). Perhaps more detailed information on CTL specificity has come from the analysis of the CTL response to hapten-modified cells (12)(13)(14)(15). Overall, these studies have demonstrated a high degree of specificity in CTL recognition of hapten-modified cell surfaces; however, it is not clear from these studies whether hapten per se is exclusively

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Section: Gtntral Male Balb/c (H-2d) and Cba/h (H-mentioning

confidence: 88%

Specificity of cytotoxicity T cells directed to influenza virus hemagglutinin.

Braciale¹

1979

The Journal of Experimental Medicine

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“…T cells are usually more cross-reactive than antibodies [4][5][6] and additionally recognize more conserved, virus-internal proteins [7,8]. Induction of broadly reactive T cells by vaccination may therefore be a potential avenue to follow [9,10].…”

Section: Introductionmentioning

confidence: 99%

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Schmitz¹,

Beerli²,

Bauer³

et al. 2012

Eur J Immunol

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A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7 -/-mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies.Keywords: Antibodies r Immunotherapy r Toll like receptors r Vaccination r Virology IntroductionInfection with influenza virus is a major cause of morbidity as well as mortality throughout the world. Influenza virus is a very dynamic pseudo species and constantly avoids immunity at the population level by accumulating mutations in the hemagglutinin (HA) and neuraminidase molecules in a process called genetic drift. In addition, in a rare process called genetic shift, human influenza viruses may reassort with avian or swine influenza viruses [1]. Since under these circumstances, the virus hits an essentially naive population, the epidemic may become a pandemic with potentially millions of people infected and killed by the virus.Correspondence: Dr. Martin F. Bachmann e-mail: martin.bachmann@me.com Induction of protective immunity against influenza virus, not affected by genetic drift or shift, is therefore a major goal in vaccine development [2,3]. T cells are usually more cross-reactive than antibodies [4][5][6] and additionally recognize more conserved, virus-internal proteins [7,8]. Induction of broadly reactive T cells by vaccination may therefore be a potential avenue to follow [9,10]. This, however, may be a difficult task, since protective T-cell responses are usually short lived in mice [11] and humans [12], and it has not been possible so far to induce long-lived T-cell mediated immunity by vaccination. An alternative approach represents the induction of protective antibody responses directed against conserved viral structures. The extracellular domain of M2 (M2e) is a candidate for such a vaccine. M2e is highly conserved in all influenza A strains and has hardly changed over the last 90 years [13,14]. Although the recently emerged pandemic influ...

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“…Humoral immune responses are represented by the production of antibodies that bind to the surfaces of bacteria and viruses, whereas cellular immune responses mediate immunity against intracellular pathogens. Since Effros et al (30) reported in 1977 that influenza A virus-specific CTLs were broadly cross-reactive against cells of the same MHC class I type that had been infected with serologically distinct H1N1 and H3N2 influenza viruses, it has been known that CTLs specific for internal proteins exhibit high cross-reactivity between strains and subtypes, reflecting an internal viral protein conservation rate of À90z (31). Lee et al (32) reported that memory T cells established in response to seasonal human influenza A infection cross-reacted with H5N1 in healthy individuals who had not been exposed to H5N1 viruses.…”

Section: Development Of a Ctl-based Universal Influenza Vaccinementioning

confidence: 99%