Enhanced Type 1 Immunity After Secondary Viral Challenge in Mice Primed as Neonates

Fadel, Shaza A; Ozaki, Daniel A.; Sarzotti, Marcella

doi:10.4049/jimmunol.169.6.3293

Cited by 23 publications

(21 citation statements)

References 43 publications

(76 reference statements)

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“…We interpret these findings as induction of RSV‐specific Th2 memory responses after neonatal RSV infection. Other investigators have shown, in a model of neonatal priming with murine leukaemia virus, a transient production of IL‐4 after secondary viral challenge [28]. However, this IL‐4 production was not virus‐specific and subsided 3 weeks after challenge.…”

Section: Discussionmentioning

confidence: 96%

Infection of mice with respiratory syncytial virus during neonatal life primes for enhanced antibody and T cell responses on secondary challenge

Tasker

Lindsay

Clarke

et al. 2008

Clinical and Experimental Immunology

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SummaryPrimary neonatal immune responses to infection or vaccines are weak when compared with those of adults. In addition, memory responses of neonatally primed animals may be absent, weak or T helper type 2 (Th2)-biased. Respiratory syncytial virus (RSV) is an important pathogen of human infants and infection during the neonatal period has been linked to the development of asthma in later life. Here we report that acute intranasal infection of neonatal mice with RSV induces significant RSV-specific antibody and CD8 T cell responses. These responses were boosted after RSV rechallenge during adulthood, demonstrating the establishment of memory after neonatal priming. Primary infection during neonatal life was associated, following rechallenge, with limited viral replication in the lung. Recall responses of both spleen and lymph node cells from neonatally primed and adult-primed mice were associated with interferon-g secretion, indicative of a Th1-type response. However, interleukin (IL)-4 and IL-5 secretion were enhanced only in spleen and lymph node cells from neonatally primed mice. Rechallenge of neonatally primed mice was also associated with increased concentrations of chemokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1a and regulated upon activation normal T cell expressed and secreted in the lung. These may play a role in the enhanced inflammatory cell recruitment and immunopathology induced following RSV reinfection. Our results demonstrate therefore that immunity to RSV can be established during neonatal life and, importantly, that the quality of the subsequent response is dependent upon the age of first infection.

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Section: Discussionmentioning

confidence: 96%

Infection of mice with respiratory syncytial virus during neonatal life primes for enhanced antibody and T cell responses on secondary challenge

Tasker

Lindsay

Clarke

et al. 2008

Clinical and Experimental Immunology

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“…CD8 + cell function in neonates has been mostly studied in response to infection with viruses, including influenza virus (25, 26), herpes simplex virus (27–29), respiratory syncytial virus (30), cytomegalovirus (31, 32), lymphocytic choriomeningitis virus (33), adenovirus (34), and Cas-Br-E murine leukemia virus (35–37). Most often, these viruses have been introduced either systemically or through a pulmonary route.…”

Section: Discussionmentioning

confidence: 99%

Rapid CD8+ Function Is Critical for Protection of Neonatal Mice from an Extracellular Bacterial Enteropathogen

Siefker

Adkins

2017

Front. Pediatr.

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Both human and murine neonates are characteristically highly susceptible to bacterial infections. However, we recently discovered that neonatal mice are surprisingly highly resistant to oral infection with Yersinia enterocolitica. This resistance was linked with activation of both innate and adaptive responses, involving innate phagocytes, CD4+ cells, and B cells. We have now extended these studies and found that CD8+ cells also contribute importantly to neonatal protection from Y. enterocolitica. Strikingly, neonatal CD8+ cells in the mesenteric lymph nodes (MLN) are rapidly mobilized, increasing in proportion, number, and IFNγ production as early as 48 h post infection. This early activation appears to be critical for protection since B2m−/− neonates are significantly more susceptible than wt neonates to primary Y. enterocolitica infection. In the absence of CD8+ cells, Y. enterocolitica rapidly disseminated to peripheral tissues. Within 48 h of infection, both the spleens and livers of B2m−/−, but not wt, neonates became heavily colonized, likely leading to their deaths from sepsis. In contrast to primary infection, CD8+ cells were dispensable for the generation of immunological memory protective against secondary infection. These results indicate that CD8+ cells in the neonatal MLN contribute importantly to protection against an extracellular bacterial enteropathogen but, notably, they appear to act during the early innate phase of the immune response.

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“…Some previous investigations into the neonatal memory response were performed using models of chronic infection. These studies found that neonate-primed CD8 + T cells develop into cells that rival adult-primed cells in proliferation and effector function in a murine leukemia virus model of chronic viral infection (47, 48). However, such chronic infections due to the sustained presence of high antigen loads do not reflect true memory, and may not be informative on memory generation after an acute infection that is followed by antigen clearance.…”

Section: Discussionmentioning

confidence: 99%

Rapid Evolution of the CD8+ TCR Repertoire in Neonatal Mice

Carey

Gracias

Thayer

et al. 2016

The Journal of Immunology

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Currently, there is little consensus regarding the most appropriate animal model to study acute infection and the virus–specific CD8+ T cell (CTL) responses in neonates. TCRβ high-throughput sequencing in naïve CTL of differently aged neonatal mice was performed, which demonstrated differential Vβ family gene usage. Using an acute influenza infection model, we examined the TCR repertoire of the CTL response in neonatal and adult mice infected with influenza type A virus. Three-day old mice mounted a greatly reduced primary NP(366–374)-specific CTL response when compared to 7-day old and adult mice, while secondary CTL responses were normal. Analysis of NP(366–374)-specific CTL TCR repertoire revealed different Vβ gene usage and greatly reduced public clonotypes in 3-day old neonates. This could underlie the impaired CTL response in these neonates. To directly test this, we examined whether controlling the TCR would restore neonatal CTL responses. We performed adoptive transfers of both non-transgenic and TCR-transgenic OVA(257–264)-specific (OT-I) CD8+ T cells into influenza-infected hosts, which revealed that naïve neonatal and adult OT-I cells expand equally well in neonatal and adult hosts. In contrast, non-transgenic neonatal CD8+ T cells when transferred into adults failed to expand. We further demonstrate that differences in TCR avidity may contribute to decreased expansion of the endogenous neonatal CTL. These studies highlight the rapid evolution of the neonatal TCR repertoire during the first week of life and show that impaired neonatal CTL immunity results from an immature TCR repertoire, rather than intrinsic signaling defects or a suppressive environment.

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Enhanced Type 1 Immunity After Secondary Viral Challenge in Mice Primed as Neonates

Cited by 23 publications

References 43 publications

Infection of mice with respiratory syncytial virus during neonatal life primes for enhanced antibody and T cell responses on secondary challenge

Infection of mice with respiratory syncytial virus during neonatal life primes for enhanced antibody and T cell responses on secondary challenge

Rapid CD8+ Function Is Critical for Protection of Neonatal Mice from an Extracellular Bacterial Enteropathogen

Rapid Evolution of the CD8+ TCR Repertoire in Neonatal Mice

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