LAG-3 Confers a Competitive Disadvantage upon Antiviral CD8 + T Cell Responses

Ongoing clinical trials are evaluating the benefits of systemic blockade of lymphocyte activation gene-3 (LAG-3) signals to improve immunity to tumors. Those studies are founded on the well-established inhibitory role of LAG-3 in regulating CD8+ T cells during chronic virus infection and anti-tumor responses. However, the T cell response in LAG-3 deficient mice is similar in size and function to that in wild type animals, suggesting LAG-3 has nuanced immune-regulatory functions. We performed a series of adoptive transfer experiments in mice to better understand the T cell-intrinsic functions of LAG-3 in the regulation of CD8+ T cell responses. Our results indicate that LAG-3 expression by CD8+ T cells inhibits their competitive fitness and results in a slightly reduced rate of cell division in comparison to LAG-3 deficient cells. This cell-intrinsic effect of LAG-3 was consistent across both acute and chronic virus infections. These data show that LAG-3 directly modulates the size of the T cell response and support the use of LAG-3 blockade regimens to enhance CD8+ T cell responses

CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

Immunological memory is a hallmark of adaptive immunity, and understanding T cell memory will be central to the development of effective cell-mediated vaccines. The characteristics and functions of CD4 memory cells have not been well defined. Here we demonstrate that the increased size of the secondary response is solely a consequence of the increased antigen-specific precursor frequency within the memory pool. Memory cells proliferated less than primary responding cells, even within the same host. By analyzing the entry of primary and memory cells into the cell cycle, we found that the two populations proliferated similarly until day 5; after this time, fewer of the reactivated memory cells proliferated. At this time, fewer of the reactivated memory cells made IL-2 than primary responding cells, but more made IFNγ. Both these factors affected the low proliferation of the memory cells, because either exogenous IL-2 or inhibition of IFNγ increased the proliferation of the memory cells

A Comment on "The Far Future of Exoplanet Direct Characterization" - the Case for Interstellar Space Probes

Following on from ideas presented in a recent paper by Schneider et al. (2010) on "The Far Future of Exoplanet Direct Characterization", I argue that they have exaggerated the technical obstacles to performing such 'direct characterization' by means of fast (order 0.1c) interstellar space probes. A brief summary of rapid interstellar spaceflight concepts that may be found in the literature is presented. I argue that the presence of interstellar dust grains, while certainly something which will need to be allowed for in interstellar vehicle design, is unlikely to be the kind of 'show stopper' suggested by Schneider et al. Astrobiology as a discipline would be a major beneficiary of developing an interstellar spaceflight capability, albeit in the longer term, and I argue that astrobiologists should keep an open mind to the possibilities.Comment: Accepted for publication in Astrobiolog

Interferon-γ acts directly on CD8+ T cells to increase their abundance during virus infection

Interferon-γ (IFNγ) is important in regulating the adaptive immune response, and most current evidence suggests that it exerts a negative (proapoptotic) effect on CD8+ T cell responses. We have developed a novel technique of dual adoptive transfer, which allowed us to precisely compare, in normal mice, the in vivo antiviral responses of two T cell populations that differ only in their expression of the IFNγ receptor. We use this technique to show that, contrary to expectations, IFNγ strongly stimulates the development of CD8+ T cell responses during an acute viral infection. The stimulatory effect is abrogated in T cells lacking the IFNγ receptor, indicating that the cytokine acts directly upon CD8+ T cells to increase their abundance during acute viral infection

B Cell Depletion Curtails CD4+ T Cell Memory and Reduces Protection against Disseminating Virus Infection

Dynamic interactions between CD4+ T cells and B cells are needed for humoral immunity and CD4+ T cell memory. It is not known whether B cells are needed early on to induce the formation of memory precursor cells or are needed later to sustain memory cells. Herein, primary and memory CD4+ T cells responses were followed in wildtype mice that were depleted of mature B cells by anti-CD20 before or different times after acute lymphocytic choriomeningitis virus (LCMV) infection. The antibody treatment led to a 1000-fold reduction in B cell number that lasted 6 weeks. Primary virus-specific CD4+ Th1 cells were generated in B cell-depleted mice, however, there was a decrease in the CD4+Ly6CloTbet+ memory precursor population and a corresponding 4-fold reduction in CD4+ memory cell number. Memory T cells showed impaired cytokine production when they formed without B cells. B cell-depletion had no effect on established memory populations. During disseminating virus infection, B cell depletion led to sustained weight loss, functional exhaustion of CD4+ and CD8+ T cells, and prevented mice from resolving the infection. Thus, B cells contribute to the establishment and survival of memory CD4+ T cells following acute infection and play an essential role in immune protection against disseminating virus infection

IFN- Exerts Opposing Effects on T Cell Responses Depending on the Chronicity of the Virus Infection

IFN-lambda (IFN-λ) induces an antiviral state in many cell types and may contribute to the overall inflammatory environment following infection. Either of these effects may influence adaptive immune responses, but the role of type-3 interferons in the development of primary and memory T cell responses to infection has not been evaluated. Herein, we examined T cell responses to acute or persistent lymphocytic choriomeningitis virus (LCMV) infection in IFN-λR1-deficient mice. Following acute infection, we find that IFN-λR1-deficient mice produced normal levels of interferon, robust NK cell responses, but greater than normal CD4+ and CD8+ T cell responses compared to WT Balb/c mice. There were more T cells that were IL-7Rhi and, correspondingly, the IFN-λR-deficient mice showed a 2–3-fold increase in memory T cell number. The inhibitory effect of IFN-λR expression was independent of direct cytokine signaling into T cells. In contrast to acute infection, the IFN-λR-deficient mice generated markedly diminished T cell responses and had greater weight loss compared to WT mice when confronted with a highly disseminating variant of LCMV. These data indicate that IFN-λR limits T cell responses and memory following transient infection but augments T cell responses during persisting infection. Thus, the immune regulatory functions for IFN-λR are complex and vary with the overall inflammatory environment

Epigenetic Dysfunction in Turner Syndrome Immune Cells

Turner syndrome (TS) is a chromosomal condition associated with partial or complete absence of the X chromosome that involves characteristic findings in multiple organ systems. In addition to well-known clinical characteristics such as short stature and gonadal failure, TS is also associated with T cell immune alterations and chronic otitis media, suggestive of a possible immune deficiency. Recently, ubiquitously transcribed tetratricopeptide repeat on the X chromosome (UTX), a histone H3 lysine 27 (H3K27) demethylase, has been identified as a downregulated gene in TS immune cells. Importantly, UTX is an X-linked gene that escapes X-chromosome inactivation and thus is haploinsufficient in TS. Mice with T cell-specific UTX deficiency have impaired clearance of chronic viral infection due to decreased frequencies of T follicular helper (Tfh) cells, which are critical for B cell antibody generation. In parallel, TS patients have decreased Tfh frequencies in peripheral blood. Together, these findings suggest that haploinsufficiency of the X-linked UTX gene in TS T cells underlies an immune deficit, which may manifest as increased predisposition to chronic otitis media

The Depletion of NK Cells Prevents T Cell Exhaustion to Efficiently Control Disseminating Virus Infection

NK cells have well-established functions in immune defense against virus infections and cancer through their cytolytic activity and production of cytokines. In this study, we examined the frequency of NK cells and their influence on T cell responses in mice given variants of lymphocytic choriomeningitis virus that cause acute or persisting infection. We found increased frequencies of circulating NK cells during disseminating infection compared with uninfected or acutely infected mice. Consistent with recent reports, we observed that the depletion of NK cells in mice with disseminated infection increased peak numbers of virus-specific cytokine producing CD8(+) T cells and resulted in the rapid resolution of disseminated infection. Additionally, we show that NK cell depletion sustained T cell responses across time and protected against T cell exhaustion. The positive effects of NK cell depletion on T cell responses only occurred when NK cells were depleted within the first 2 d of infection. We find that the improved CD8(+) T cell response correlated with an enhanced ability of APCs from NK cell-depleted mice to stimulate T cell proliferation, independently of the effects of NK cells on CD4(+) T cells. These results indicate that NK cells play an integral role in limiting the CD8 T cell response and contribute to T cell exhaustion by diminishing APC function during persisting virus infection

Editorial: The role of adipose tissue and resident immune cells in infections

Adipose tissues are distributed throughout the body and are in direct contact with sites of infection entry, such as mucosal tissues, gut, and skin. There is increasing appreciation that adipose tissue can influence local and systemic immune responses to infection. The adipose tissue can modulate immune responses through changes in the expression of pro- and anti-inflammatory cytokines, adipokines, and hormones that regulate general metabolism. Immune cells within adipose show differentiation states that are distinct from those in circulation or in lymphoid tissues, suggesting that the adipose environment regulates immune cell activity. The mechanisms leading to immune cell recruitment and maintenance within adipose remain enigmatic. Changes in diet that lead to obesity can alter the frequencies of regulatory or effector cells within adipose, potentially affecting local and systemic immune protection. Obesity is associated with higher susceptibility to infections possibly due to alterations in immune cells residing in adipose tissue. The interplay between immune cells and adipose is complex and bi-directional: immune cells residing within adipose tissue can perturb adipose tissue homeostasis and whole-body metabolism and, conversely, metabolic cues can modulate immune responses. Several reports demonstrate that microorganisms can target and even persist in adipose tissues. However, relatively few studies have addressed the immunological consequences of adipose tissue infection

Nemesis Reconsidered

The hypothesis of a companion object (Nemesis) orbiting the Sun was motivated by the claim of a terrestrial extinction periodicity, thought to be mediated by comet showers. The orbit of a distant companion to the Sun is expected to be perturbed by the Galactic tidal field and encounters with passing stars, which will induce variation in the period. We examine the evidence for the previously proposed periodicity, using two modern, greatly improved paleontological datasets of fossil biodiversity. We find that there is a narrow peak at 27 My in the cross-spectrum of extinction intensity time series between these independent datasets. This periodicity extends over a time period nearly twice that for which it was originally noted. An excess of extinction events are associated with this periodicity at 99% confidence. In this sense we confirm the originally noted feature in the time series for extinction. However, we find that it displays extremely regular timing for about 0.5 Gy. The regularity of the timing compared with earlier calculations of orbital perturbation would seem to exclude the Nemesis hypothesis as a causal factor.Comment: 10 pages, 2 figures, accepted for publication in Monthly Notices of the Royal Astronomical Societ