CD4 T cells provide protection against cytomegalovirus (CMV) and other persistent viruses, and the ability to quantify and characterize epitope-specific responses is essential to gain a more precise understanding of their effector roles in this regard. Here, we report the first two I-A d -restricted CD4 T cell responses specific for mouse CMV (MCMV) epitopes and use a major histocompatibility complex class II (MHC-II) tetramer to characterize their phenotypes and functions. We demonstrate that MCMV-specific CD4 T cells can express high levels of granzyme B and kill target cells in an epitope-and organ-specific manner. In addition, CD4 T cell epitope vaccination of immunocompetent mice reduced MCMV replication in the same organs where CD4 cytotoxic T lymphocyte (CTL) activity was observed. Together, our studies show that MCMV epitope-specific CD4 T cells have the potential to mediate antiviral defense by multiple effector mechanisms in vivo. C ytomegalovirus (CMV)/human herpesvirus 5 (HHV-5) (the prototypic betaherpesvirus) infection is endemic in humans and wild mice and establishes a lifelong infection in the absence of acute disease in healthy hosts. Adaptive immunity is a critical component of CMV defenses, restricting primary infection and dampening reactivation, helping to maintain the largely benign host-virus equilibrium. However, if immunity is naive or compromised (e.g., in transplant recipients or congenital infection), CMV can cause serious disease (1, 2). In immunocompetent mice, CD8 T cells help to control acute CMV infection and establish latency (3, 4), and their adoptive transfer prevents disease in mice and humans with weakened immunity (5-8). Although much less well studied, CD4 T cells also contribute to defense against CMV. Their rapid expansion and numbers correlate with reduced disease in transplant and HIV patients (9-11), and correspondingly, delayed induction of CMV-specific CD4 T cells is associated with increased congenital infection (12) and prolonged viral shedding in infants (13). Notably, no protective correlates were seen with CMV-specific CD8 T cell responses in several of these studies. In mice, CD4 T cells are absolutely required to control mouse cytomegalovirus (MCMV) replication in the salivary glands-the key site of viral dissemination, where CD8 T cells can exert no control (14, 15)-and also contribute to immune control in several other organs. Adoptive transfer of MCMV-specific transgenic CD4 T cells provides some protection in immunocompromised mice (16), and cotransferring CMV-specific CD4 T cells reduces viral load and promotes "help" for CMV-specific CD8 T cell responses in patients receiving cellular immunotherapy (17).In addition to traditional helper functions, CD4 T cells can also mediate direct antiviral activity in some cases. In chronic human CMV (HCMV), Epstein-Barr virus (EBV), and HIV infections, CD4 T cells displaying a terminally differentiated effector phenotype and/or expressing canonical cytolytic molecules (e.g., granzymes and perforin) are pres...
Cardiomyocytes of newborn mice proliferate after injury or exposure to growth factors. However, these responses are diminished after postnatal day-6 (P6), representing a barrier to building new cardiac muscle in adults. We have previously shown that exogenous thyroid hormone (T3) stimulates cardiomyocyte proliferation in P2 cardiomyocytes, by activating insulin-like growth factor-1 receptor (IGF-1R)-mediated ERK1/2 signaling. But whether exogenous T3 functions as a mitogen in post-P6 murine hearts is not known. Here, we show that exogenous T3 increases the cardiomyocyte endowment of P8 hearts, but the proliferative response is confined to cardiomyocytes of the left ventricular (LV) apex. Exogenous T3 stimulates proliferative ERK1/2 signaling in apical cardiomyocytes, but not in those of the LV base, which is inhibited by expression of the nuclear phospho-ERK1/2-specific dual-specificity phosphatase, DUSP5. Developmentally, between P7 and P14, DUSP5 expression increases in the myocardium from the LV base to its apex; after this period, it is uniformly expressed throughout the LV. In young adult hearts, exogenous T3 increases cardiomyocyte numbers after DUSP5 depletion, which might be useful for eliciting cardiac regeneration.
The current vaccine against tuberculosis (TB), Mycobacterium bovis BCG, fails to protect against the most prevalent disease form, pulmonary TB in adults. It is generally assumed that active TB occurs because of a weakening of the immune system, which keeps Mycobacterium tuberculosis in check as long as it is fully competent. M. tuberculosis does not induce the optimum protection because the pathogen is not eradicated, and it has now been shown that exogenous reinfection does occur, suggesting that natural immunity is insufficient (26) and fails to control the pathogen in the long run. Hence, other mycobacterial strains which share cross-reactive antigens (Ags) with M. tuberculosis have also been considered as alternatives to M. bovis for vaccine use. One strain, "Mycobacterium w," had been evaluated for its immunomodulatory properties in leprosy. M. w is a nonpathogenic, cultivable mycobacterium (18) which has been found to improve immunity to leprosy (30). A vaccine against leprosy based on M. w is approved for human use, where it has resulted in clinical improvement, accelerated bacterial clearance, and increased immune responses to Mycobacterium leprae Ags (13,21,25). M. w shares Ags not only with M. leprae but also with M. tuberculosis (29), and initial studies have shown that vaccination with killed M. w induces protection against TB in animal models (22, 23) and also resulted in early sputum conversion in TB patients (17). Recently it has been suggested that M. w be referred to as Mycobacterium indicus pranii to avoid confusion with M. tuberculosis-W (Beijing strain) (24). It is generally known that live bacteria impart greater protection than killed bacteria. It may be that persistence of live bacteria in the host for some time results in a robust memory response (12). Another important factor is that secretory proteins which are absent in the killed bacterial vaccines have been shown to play an important role in protection. In this study, we analyzed the M. tuberculosis-specific immune response induced in mice immunized with live or killed M. w and compared it with the BCG-induced immune response and also compared the protective efficacies of the two mycobacteria.As the lung is the primary target organ of this disease, immunization potential by the aerogenic route was also studied. Inhalation of aerosols provides a noninvasive delivery system that physically targets the lung as the desired site of the pharmacological effect. This route of immunization has emerged a very attractive route of vaccine delivery, inducing both local and systemic immunity (7, 10).
BackgroundThe 9-month-long chemotherapy of tuberculosis often results in poor compliance and emergence of drug-resistant strains. So, improved therapeutic strategy is urgently needed. Immunotherapy could be beneficial for the effective management of the disease. Previously we showed the protective efficacy of Mycobacterium indicus pranii (MIP) when given as prophylactic vaccine in animal models of tuberculosis.MethodsWe sought to investigate whether MIP can be used as an adjunct to the chemotherapy in guinea pig models of tuberculosis. Efficacy of MIP was evaluated when given subcutaneously or by aerosol.ResultsMIP-therapy as an adjunct to the chemotherapy was found to be effective in accelerating bacterial killing and improving organ pathology. MIP-immunotherapy resulted in higher numbers of activated antigen-presenting cells and lymphocytes in the infected lungs and also modulated the granulomatous response. Early increase in protective Th1 immune response was observed in the immunotherapy group. Following subsequent doses of MIP, decrease in the inflammatory response and increase in the immunosuppressive response was observed, which resulted in the improvement of lung pathology.ConclusionMIP immunotherapy is a valuable adjunct to chemotherapy for tuberculosis. Aerosol route of immunotherapy can play a crucial role for inducing immediate local immune response in the lung.
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