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Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus--host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire. [ABSTRACT FROM AUTHOR]

In response to infection, naïve CD8+ T (TN) cells yield a large pool of short-lived terminal effector (TTE) cells that eliminate infected host cells. In parallel, a minor population of stem cell–like central memory (TCM) cells forms, which has the capacity to maintain immunity after pathogen clearance. It has remained uncertain whether stem-like TCM cells arise by dedifferentiation from a subset of cytolytic TTE cells or whether priming generates stem-like cells capable of seeding the TCM compartment and, if so, when cytolytic TTE cells branch off. Here, we show that CD8+ T cells with stem-like properties, which are identified by the expression of TCF1 (encoded by Tcf7), are present across the primary response to infection. Priming programs TN cells to undergo multiple cell divisions, over the course of which TCF1 expression is maintained. These TCF1+ cells further expand relatively independently of systemic inflammation, antigen dose, or affinity, and they quantitatively yield TCF1+ TCM cells after pathogen clearance. Inflammatory signals suppress TCF1 expression in early divided TCF1+ cells. TCF1 down-regulation is associated with the irreversible loss of self-renewal capacity and the silencing of stem/memory genes, which precedes the stable acquisition of a TTE state. TCF1 expression restrains cell cycling, explaining in part the limited expansion of TCF1+ relative to TCF1− cells during the primary response. Thus, our data are consistent with terminal differentiation of effector cells being a step-wise process that is initiated by inflammation in primed stem-like cells, which would otherwise become central memory cells by default. Editor's summary: The adaptive immune system is characterized by the ability to generate long-lived memory cells that provide protection against reinfection. Yet it is uncertain how a pool of stem-cell like central memory T cells (TCM) develops after pathogen encounter. Silva et al. used mouse models to track the emergence and fate of central memory precursor T cells (TpCM) during the first exposure to lymphocytic choriomeningitis virus (LCMV). These TpCM were detected early after infection, were present throughout the acute phase of the immune response, and were predisposed to become TCM, although they could form effector T cells when exposed to inflammatory signals. Additionally, the ability to generate TpCM in response to certain vaccination models indicates conditions that might instruct the formation of immune memory optimally. —Sarah H. Ross [ABSTRACT FROM AUTHOR]

Previous studies that used peptide‐MHC (pMHC) tetramers (tet) to identify self‐specific T cells have questioned the effectiveness of thymic‐negative selection. Here, we used pMHCI tet to enumerate CD8 T cells specific for the immunodominant gp33 epitope of lymphocytic choriomeningitis virus glycoprotein (GP) in mice transgenically engineered to express high levels of GP as a self‐antigen in the thymus. In GP‐transgenic mice (GP+), monoclonal P14 TCR+ CD8 T cells that express a GP‐specific TCR could not be detected by gp33/Db‐tet staining, indicative of their complete intrathymic deletion. By contrast, in the same GP+ mice, substantial numbers of polyclonal CD8 T cells identifiable by gp33/Db‐tet were present. The gp33‐tet staining profiles of polyclonal T cells from GP+ and GP‐negative (GP−) mice were overlapping, but mean fluorescence intensities were ∼15% lower in cells from GP+ mice. Remarkably, the gp33‐tet+ T cells in GP+ mice failed to clonally expand after lymphocytic choriomeningitis virus infection, whereas those of GP− mice did so. In Nur77GFP‐reporter mice, dose‐dependent responses to gp33 peptide‐induced TCR stimulation revealed that gp33‐tet+ T cells with high ligand sensitivity are lacking in GP+ mice. Hence, pMHCI tet staining identifies self‐specific CD8 T cells but tends to overestimate the number of truly self‐reactive cells. [ABSTRACT FROM AUTHOR]

Background: A vaccine (HB-101) consisting of 2 nonreplicating lymphocytic choriomeningitis virus (LCMV) vectors expressing the human cytomegalovirus antigens glycoprotein B (gB) and the 65-kD phosphoprotein (pp65), respectively, is in development to prevent cytomegalovirus infection.Methods: HB-101 was tested in cytomegalovirus-naive, healthy adults in a randomized, double-blind, placebo-controlled, dose-escalation Phase I trial. Fifty-four subjects received low, medium, or high dose of HB-101 or placebo by intramuscular administration at Month 0, 1, and 3. Safety and immunogenicity were the respective primary and secondary endpoints. Subjects were followed for 12 months after the initial immunization.Results: Vaccination was associated with transient mild to moderate adverse events. HB-101 administration induced dose-dependent gB- and pp65-specific cellular responses, dominated by pp65-specific CD8 T cells, a high fraction of which were polyfunctional. Two administrations were sufficient to elicit dose-dependent gB-binding and cytomegalovirus-neutralizing antibodies (Abs). Cytomegalovirus-specific immune responses were boosted after each administration. Only 1 of 42 vaccine recipients mounted a transient LCMV vector-neutralizing Ab response.Conclusions: HB-101 was well tolerated and induced cytomegalovirus-specific polyfunctional CD8 T-cell and neutralizing Ab responses in the majority of subjects. Lack of vector-neutralizing Ab responses should facilitate booster vaccinations. These results justify further clinical evaluation of this vaccine candidate. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are often precipitated by viral infections. Yet our current understanding fails to explain how viruses trigger organ-specific autoimmunity despite thymic tolerance extending to many nonlymphohematopoietic self antigens. Additionally, [...]