Depletion of T Cells by Type I Interferon: Differences between Young and Aged Mice

Jiang, Jiu; Gross, D. J.; Nogusa, Shoko; Elbaum, Philip; Murasko, Donna M.

doi:10.4049/jimmunol.175.3.1820

Cited by 37 publications

(40 citation statements)

References 48 publications

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“…We have no explanation for that finding, but it was highly reproducible in three separate experiments. As expected, the acute MCMV infection caused a reduction in the frequency and number of LCMV-specific memory T cells, probably as a consequence of the well-defined type I IFN-induced apoptosis of memory cells early during many infections (10,(13)(14)(15)(16)(17)(18); indeed, we confirmed that there was a substantial very early loss of memory CD8 T cells in this study (Fig. 1a and b).…”

Section: Discussionsupporting

confidence: 78%

Heterologous Immunity and Persistent Murine Cytomegalovirus Infection

Jenny

Daniels

Selin

et al. 2017

J Virol

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One's history of infections can affect the immune response to unrelated pathogens and influence disease outcome through the process of heterologous immunity. This can occur after acute viral infections, such as infections with lymphocytic choriomeningitis virus (LCMV) and vaccinia virus, where the pathogens are cleared, but it becomes a more complex issue in the context of persistent infections. In this study, murine cytomegalovirus (MCMV) was used as a persistent infection model to study heterologous immunity with LCMV. If mice were previously immune to LCMV and then infected with MCMV (LCMVϩMCMV), they had more severe immunopathology, enhanced viral burden in multiple organs, and suppression of MCMV-specific T cell memory inflation. MCMV infection initially reduced the numbers of LCMV-specific memory T cells, but continued MCMV persistence did not further erode memory T cells specific to LCMV. When MCMV infection was given first (MCMVϩLCMV), the magnitude of the acute T cell response to LCMV declined with age though this age-dependent decline was not dependent on MCMV. However, some of these MCMV persistently infected mice with acute LCMV infection (7 of 36) developed a robust immunodominant CD8 T cell response apparently cross-reactive between a newly defined putative MCMV epitope sequence, M57 [727][728][729][730][731][732][733][734] , and the normally subdominant LCMV epitope L 2062-2069 , indicating a profound private specificity effect in heterologous immunity between these two viruses. These results further illustrate how a history of an acute or a persistent virus infection can substantially influence the immune responses and immune pathology associated with acute or persistent infections with an unrelated virus. IMPORTANCE This study extends our understanding of heterologous immunity in the context of persistent viral infection. The phenomenon has been studied mostly with viruses such as LCMV that are cleared, but the situation can be more complex with a persistent virus such as MCMV. We found that the history of LCMV infection intensifies MCMV immunopathology, enhances MCMV burden in multiple organs, and suppresses MCMV-specific T cell memory inflation. In the reverse infection sequence, we show that some of the long-term MCMV-immune mice mount a robust CD8 T cell cross-reactive response between a newly defined putative MCMV epitope sequence and a normally subdominant LCMV epitope. These results further illustrate how a history of infection can substantially influence the immune responses and immune pathology associated with infections with an unrelated virus. KEYWORDS CD8 T cell, memory inflation, heterologous immunity, cross-reactivity, lymphocytic choriomeningitis virus, murine cytomegalovirus, mouse H eterologous immunity, that is, the ability of immunological memory specific to one pathogen to contribute to the control of a different pathogen, has been an established immunological phenomenon since Edward Jenner used cowpox virus to immunize against variola virus, the cause of human small...

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Section: Discussionsupporting

confidence: 78%

Heterologous Immunity and Persistent Murine Cytomegalovirus Infection

Jenny

Daniels

Selin

et al. 2017

J Virol

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“…Instead, aged naïve CD4 T cells were inherently resistant to spontaneous apoptosis and apoptosis induced in vitro by corticosteroids, serum removal, TNF-␣, and FasL. An increase in mature B-cell lifespan has been inferred based on the decrease in progenitors and lower rates of turnover with aging (34), and aged naïve CD8 T cells have been reported to turn over more slowly than younger cells and to be refractory to apoptosis induced by type I IFN and by growth/ survival factor withdrawal (35,36), suggesting this pathway might influence other lymphocytes and might be already programmed by epigenetic changes in aged hematopoietic stem cells.…”

Section: Discussionmentioning

confidence: 99%

Age-associated increase in lifespan of naïve CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects

Tsukamoto

Clise-Dwyer

Huston

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

131

158

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With age, T-cell generation from the thymus is much reduced, yet a substantial naïve T-cell pool is maintained even in aged animals, suggesting that naïve T cells either persist longer or turn over faster to maintain T-cell homeostasis. We found that with age, naïve CD4 T cells became progressively longer-lived. Their longer lifespan did not depend on recognition of self-peptide/class II. Newly generated naïve T cells derived from aged stem cells had a shorter lifespan, like that of young naïve T cells. Conversely, naïve CD4 T cells derived from middle-aged thymectomized mice were longer-lived in vivo, and their development of functional defects was accelerated. These observations suggest that naïve T cells develop their longer lifespan during their sojourn in the periphery. Increased longevity of naïve CD4 T cells correlated well with reduced expression of proapoptotic molecule Bim. We suggest that the intrinsic increase in longevity helps maintain naïve T-cell homeostasis but facilitates the development of functional defects in mice.aging ͉ Bim ͉ T lymphocytes ͉ apoptosis A ging is accompanied by pleiotropic changes in the immune system that lead to dysfunction of cellular and humoral immune responses (1, 2). The progressive decline in functions is associated with increased susceptibilities to infectious disease, autoimmune disease, and cancer (3-5). Naïve CD4 T cells from aged animals exhibit age-related decreases in Ag responsiveness, characterized by weak proliferative response, lower IL-2 production, and a poor ability to help B cells, leading to reduced specific antibody production (6-8). Similar functional defects are observed when aged naïve CD4 T cells are transferred to young hosts (9, 10), indicating that many of the aged-related defects are intrinsic to the naïve CD4 T cells.When depletion of naïve CD4 T cells with an endogenous superantigen (11), by anti-CD4 Ab given systemically, or by lethal irradiation followed by aged bone marrow (BM) reconstitution, leads to reconstitution of naïve T cells in aged mice, the newly generated CD4 T cells function much like cells from young mice, even though they are derived from aged stem cells (10,12,13). This suggests age-associated loss of function occurs primarily while naïve CD4 T cells persist in periphery. However, no particular mechanism(s) leading to such dysfunction has been identified.The size of the naïve T-cell population is determined by the rate of emigration of new naïve T cells from thymus and by homeostatic turnover of T cells in the periphery. T-cell homeostasis has been assumed to be achieved largely by T-cell receptor (TCR) engagement with self-peptide/MHC (14, 15) and homeostatic survival factors, such as 17). Another important component is cellular lifespan, which has often been considered a cell-intrinsic property. The homeostatic equilibriums that regulate the size of the naïve T-cell pool in aged animals may differ from those in young. Thymic involution starts at puberty and causes an abrupt decline of at least 10-fold in new thymic emig...

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“…61,63,64 Many viral infections in mouse and human induce a substantial loss in lymphocyte and leukocyte numbers in the early stages of infections. 65 A substantial loss in CD8 and CD4 T cell number during the first 5 days of LCMV infection parallels the levels of type 1 IFN production, does not occur in type 1 IFN receptor ko mice, 66 is blocked by antibody to type 1 IFN 67 and is mimicked by IFN-inducing toll receptor agonists, such as poly I:C. 66 The apoptotic loss of memory occurs prior to cell division. 63,66,68 An in silico virtual immune system model, IMMSIM, which unlike a biological system can selectively turn off either active or passive attrition, predicted that without the active attrition and apoptosis of memory T cells early in infection, crossreactive T cells might overwhelmingly dominate the response to an infection.…”

Section: Heterologous Immunity and T Cell Crossreactivitymentioning

confidence: 99%

Vaccination and heterologous immunity: educating the immune system

Gil¹,

Kenney²,

Mishra³

et al. 2015

Transactions of the Royal Society of Tropical Medicine and Hygiene

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This review discusses three inter-related topics: (1) the immaturity of the neonatal and infant immune response; (2) heterologous immunity, where prior infection history with unrelated pathogens alters disease outcome resulting in either enhanced protective immunity or increased immunopathology to new infections, and (3) epidemiological human vaccine studies that demonstrate vaccines can have beneficial or detrimental effects on subsequent unrelated infections. The results from the epidemiological and heterologous immunity studies suggest that the immune system has tremendous plasticity and that each new infection or vaccine that an individual is exposed to during a lifetime will potentially alter the dynamics of their immune system. It also suggests that each new infection or vaccine that an infant receives is not only perturbing the immune system but is educating the immune system and laying down the foundation for all subsequent responses. This leads to the question, is there an optimum way to educate the immune system? Should this be taken into consideration in our vaccination protocols?

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Depletion of T Cells by Type I Interferon: Differences between Young and Aged Mice

Cited by 37 publications

References 48 publications

Heterologous Immunity and Persistent Murine Cytomegalovirus Infection

Heterologous Immunity and Persistent Murine Cytomegalovirus Infection

Age-associated increase in lifespan of naïve CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects

Vaccination and heterologous immunity: educating the immune system

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