Lassa fever: implications of T-cell immunity for vaccine development.

Lassa fever is a re-emerging viral hemorrhagic fever, which causes significant human morbidity in endemic regions of West Africa. Attempts to vaccinate against this virus in animal models including non-human primates have revealed that eliciting a strong cellular immune response protects from clinical disease, but not infection, in the absence of measurable neutralizing antibodies. As there is renewed interest in developing a vaccine against Lassa fever for use in humans, several questions should be addressed in view of the scarce knowledge of the mechanisms of natural immunity against this disease. MHC-dependency of a vaccine relying mainly on the induction of T-cell immunity and its ability to cross-protect against different Lassa virus strains will be important issues. Furthermore, the question whether the vaccine can prevent human-to-human transmission of the virus should be discussed and the possibility that vaccination could predispose to immunopathology should be excluded. We are addressing some of the above mentioned problems concerning natural immunity through field studies in the Republic of Guinea, West Africa, and are presently studying the CD4 cell responses of Lassa antibody positive subjects on the basis of T-cell proliferation assays using recombinant Lassa virus proteins.     

Translating innate immunity into immunological memory: implications for vaccine development

Vaccination is the most effective means of preventing infectious diseases. Despite the success of many vaccines, there is presently little knowledge of the immunological mechanisms that mediate their efficacy. Such information will be critical in the design of future vaccines against old and new infectious diseases. Recent advances in immunology are beginning to provide an intellectual framework with which to address fundamental questions about how the innate immune system shapes adaptive immunity. In this review, we summarize current knowledge about how the innate immune system modulates the quantity and quality of long-term T and B cell memory and protective immune responses to pathogens. In addition, we point out unanswered questions and identify critical challenges, the solution of which, we believe, will greatly facilitate the rational design of novel vaccines against a multitude of emerging infections.     

Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation

Immune responses to infection are optimally designed to generate large numbers of effector T cells while simultaneously minimizing the collateral damage of their potentially lethal actions and generating memory T cells to protect against subsequent encounter with pathogens. Much remains to be discovered about how these equally essential processes are balanced to enhance health and longevity and, more specifically, what factors control effector T cell expansion, differentiation, and memory cell formation. The innate immune system plays a prominent role in the delicate balance of these decisions. Insights into these questions from recent work in the area of effector CD8 T cell differentiation will be discussed.     

A model T-cell receptor system for studying memory T-cell development

When T-cell clones were first grown in long-term cell culture, each clone was considered to be capable of displaying a limited range of functional activities, constrained by the clones' coreceptor, CD4 or CD8, and the specificity of its antigen-specific receptor (TCR) for one or a few peptides in association with a class I or class II MHC molecule. Subsequent studies, especially with transgenic mice, have shown, however, that T cells expressing the same receptor can be obtained in a variety of differentiated states, including na?ve cells, activated effector cells, memory cells, and anergic or tolerant cells, as well as cells with or without a coreceptor. In each of these states T cells can display distinctly different responses to the peptide-MHC (pepMHC) complexes the TCR recognizes. Recently, memory T cells have received considerable attention, in part because of the likelihood that they confer long-term protective immunity against diverse infectious agents and possibly against some forms of cancer. Here we review some recent studies that our colleagues and we have carried out on memory CD8(+) T cells. These studies have made extensive use of cells that express the TCR called 2C. The diverse set of cells expressing the 2C TCR, in mice and in cultured clones and cell lines, are referred to as the 2C system. Before reviewing the studies of memory cells, we summarize the 2C system's main features, including evidence that a large and diverse array of pepMHC complexes, involving at least four class I MHC proteins, can stimulate TCR-mediated responses of 2C cells.     

Immune response against Mycobacterium tuberculosis: implications for vaccine development

Tuberculosis remains a major health problem globally. Although this threat would best be controlled by a combination of chemotherapy and vaccination, satisfactory vaccines are not available yet. Rational design of a novel vaccine generation against tuberculosis has become possible on the basis of recent achievements in molecular genetics of the pathogen and immunology of the host. Currently, two different strategies are pursued. First, the subunit vaccine approach attempting to induce efficacious immunity by unique antigens in defined adjuvants. Second, the whole bacterial vaccine approach relying on multiple antigens and built-in adjuvanticity. Time will tell which type of vaccine is best suited for eradication of tuberculosis.     

Effector T cell differentiation and memory T cell maintenance outside secondary lymphoid organs

Naive T cell circulation is restricted to secondary lymphoid organs. Effector and memory T cells, in contrast, acquire the ability to migrate to nonlymphoid tissues. In this study we examined whether nonlymphoid tissues contribute to the differentiation of effector T cells to memory cells and the long-term maintenance of memory T cells. We found that CD4, but not CD8, effector T cell differentiation to memory cells is impaired in adoptive hosts that lack secondary lymphoid organs. In contrast, established CD4 and CD8 memory T cells underwent basal homeostatic proliferation in the liver, lungs, and bone marrow, were maintained long-term, and functioned in the absence of secondary lymphoid organs. CD8 memory T cells found in nonlymphoid tissues expressed both central and effector memory phenotypes, whereas CD4 memory T cells displayed predominantly an effector memory phenotype. These findings indicate that secondary lymphoid organs are not necessary for the maintenance and function of memory T cell populations, whereas the optimal differentiation of CD4 effectors to memory T cells is dependent on these organs. The ability of memory T cells to persist and respond to foreign Ag independently of secondary lymphoid tissues supports the existence of nonlymphoid memory T cell pools that provide essential immune surveillance in the periphery.     

Mechanisms of immunity in hydatid disease: implications for vaccine development

The Echinococcus organisms, the cause of echinococcosis (hydatid disease), are parasitic helminths with life cycles involving a carnivorous definitive host (usually dog or fox) and an intermediate host (human, ungulate, or rodent). They are complex multicellular pathogens that, despite being under constant barrage by the immune system, are able to modulate antiparasite immune responses and persist and flourish in their mammalian hosts. Understanding how the immune system deals with these parasites is a major challenge. Recent application of modern molecular and immunological approaches has revealed insights on the nature of immune responses generated during the course of hydatid infection, although many aspects of the Echinococcus-host interplay remain unexplored. This review summarizes current understanding of the immunology of echinococcosis, indicates areas where information is lacking, and shows how knowledge of host protective immunity has been translated into the design and development of anti-Echinococcus vaccines for application in intermediate hosts.     

Bacterial interplay at intestinal mucosal surfaces: implications for vaccine development

The discovery of 'molecular syringes' in several important gastrointestinal pathogens including Escherichia coli, Salmonella, Shigella and Yersinia, together with a better understanding of M cells and the mucosal immune system, has advanced our appreciation of multistage microorganism-host cell interactions. Recent studies suggest that these molecular strategies could be adapted for the development of modular mucosal vaccines.     

幽门螺杆菌感染引起的免疫应答及其对疫苗研制的启示

幽门螺杆菌是一种全世界范围的人类感染病原菌,人感染该菌后可以被诱导产生较强的体液免疫应答和一定程度的细胞免疫应答反应;但是,自然感染往往不能使机体产生有效的免疫保护,相反可引起对机体的免疫病理损伤,有效的疫苗应该被设计为能够诱导机体产生非病理损伤的特异的免疫保护反应,以此来预防和治疗幽门螺杆菌相关性疾病。本综述了这些方面的研究进展。     

Functional analysis of Plasmodium falciparum merozoite antigens: implications for erythrocyte invasion and vaccine development

Malaria is a major human health problem and is responsible for over 2 million deaths per year. It is caused by a number of species of the genus Plasmodium, and Plasmodium falciparum is the causative agent of the most lethal form. Consequently, the development of a vaccine against this parasite is a priority. There are a number of stages of the parasite life cycle that are being targeted for the development of vaccines. Important candidate antigens include proteins on the surface of the asexual merozoite stage, the form that invades the host erythrocyte. The development of methods to manipulate the genome of Plasmodium species has enabled the construction of gain-of-function and loss-of-function mutants and provided new strategies to analyse the role of parasite proteins. This has provided new information on the role of merozoite antigens in erythrocyte invasion and also allows new approaches to address their potential as vaccine candidates.     

IL-12 is required for induction but not maintenance of protective, memory responses to Blastomyces dermatitidis: implications for vaccine development in immune-deficient hosts

Cellular immunity mediated by T lymphocytes, in particular CD4(+) and CD8(+) type 1 (T1) cells, is the main defense against pathogenic fungi. IL-12 initiates T1 cell development and cell-mediated immunity, but it is unclear whether IL-12 contributes to the maintenance of an antifungal T1 response. In this study, we addressed the role of IL-12 for vaccine-induced memory T cell development against experimental pulmonary blastomycosis. CD4(+) T cells absolutely required IL-12 to control a live genetically engineered attenuated strain of Blastomyces dermatitidis given s.c. as a vaccine, whereas CD8(+) T cells were significantly less dependent on IL-12. Despite differential dependency of T cell subsets on IL-12 during vaccination, neither subset acquired memory immunity in the absence of IL-12. In contrast, adoptive transfer of immune CD4 T cells from wild-type mice into IL-12(-/-) mice showed that CD4(+) T1 memory cells sustained a T1 cytokine profile and remained protective over a period of 6 mo posttransfer. Similarly, memory CD8 cells elicited in IL-12(-/-) mice with killed yeast and transient rIL-12 treatment (during vaccination) remained durable and protective after animals were rested for 3 mo. In conclusion, these studies demonstrate that once CD4 and CD8 cells have acquired a protective T1 phenotype they no longer require the presence of IL-12 to maintain antifungal protective memory.     

Field studies of cytotoxic T lymphocytes in malaria infections: implications for malaria vaccine development

The search for a cytotoxic T lymphocyte (CTL)-inducing malaria vaccine has moved forward from epitope identification to planning stages of safety and immunogenicity trials of candidate vaccines. Development of CTL-inducing vaccine candidates has taken center stage based on the observation that CTL-mediated protection might be the dominant mechanism by which sterile immunity is achieved in irradiated sporozoite immunization experiments in humans and laboratory animals. However, studies in naturally infected individuals living in endemic areas, as reviewed here by Michael Aidoo and Venkatachalam Udhayakumar, have revealed that CTL induction might be influenced by factors such as parasite variants, host genes, other infections and transmission patterns. The influence of these factors on CTL induction has been demonstrated individually and in various combinations in controlled animal experiments. However, in naturally infected humans, they are presented in a complex host-parasite-environment interaction, in a manner that is not easily achieved in laboratory-based experiments. Understanding these interactions is crucial for the development and testing of CTL-inducing vaccines for humans.     

Soluble mediators of inflammation in HIV and their implications for therapeutics and vaccine development

From early in the HIV epidemic it was appreciated that many inflammatory markers such as neopterin and TNF-α were elevated in patients with AIDS. With the advent of modern technology able to measure a broad array of cytokines, we now know that from the earliest points of infection HIV induces a cytokine storm. This review will focus on how cytokines are disturbed in HIV infection and will explore potential therapeutic uses of cytokines. These factors can be used directly as therapy during HIV infection, either to suppress viral replication or prevent deleterious immune effects of infection, such as CD4+ T cell depletion. Cytokines also show great promise as adjuvants in the development of HIV vaccines, which would be critical for the eventual control of the epidemic.     

Metabolic memory: mechanisms and implications for diabetic vasculopathies

In the past decades, a persistent progression of diabetic vascular complications despite reversal of hyperglycemia has been observed in both experimental and clinical studies. This durable effect of prior hyperglycemia on the initiation and progression of diabetic vasculopathies was defined as “metabolic memory”. Subsequently, enhanced glycation of cellular proteins and lipids, sustained oxidative stress, and prolonged inflammation were demonstrated to mediate this phenomenon. Recently, emerging evidence strongly suggests that epigenetic modifications may account for the molecular and phenotypic changes associated with hyperglycemic memory. In this review, we presented an overview on the discovery of metabolic memory, the recent progress in its molecular mechanisms, and the future implications related to its fundamental research and clinical application.