A γ-herpesvirus sneaks through a CD8+ T cell response primed to a lytic-phase epitope

To determine whether established CD8(+) T cell memory to an epitope prominent during the replicative phase of a gamma-herpesvirus infection protects against subsequent challenge, mice were primed with a recombinant vaccinia virus expressing the p56 peptide and then boosted by intranasal exposure to an influenza A virus incorporating p56 in the neuraminidase protein. Clonally expanded populations of functional, p56-specific CD8(+) T cells were present at high frequency in both the lung and the lymphoid tissue 1 month later, immediately before respiratory challenge with gammaHV-68. This prime-and-boost regime led to a massive reduction of productive gammaHV-68 infection in the respiratory tract and, initially, to much lower levels of latency in both the regional lymph nodes and the spleen. The CD8(+) T cell response to another epitope (p79) was diminished, there was less evidence of B cell activation, and the onset of the CD4(+) T cell-dependent splenomegaly was delayed. Within 3-4 weeks of the gammaHV-68 challenge, however, the extent of latent infection in the lymph nodes and spleen was equivalent, and both groups developed the prominent infectious mononucleosis-like syndrome that is characteristic of this infection. The reverse protocol (influenza then vaccinia) seemed to be slightly less effective. Even though immune CD8(+) T cells may be present at the time and site of virus challenge, establishing a high level of CD8(+) T cell memory to lytic-phase epitopes alone does not protect against the longer-term consequences of this gammaHV infection.     

Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation

Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (T(RM)) cells are identified by their expression of the α-chain from the integrin α(E)(CD103)β(7), and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103(+)CD8(+) T(RM) cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the T(RM) phenotype. The CD8(+) T(RM) cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral T(RM) cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection.     

Measuring the diaspora for virus-specific CD8+ T cells

The CD8(+) T cell diaspora has been analyzed after secondary challenge with an influenza A virus that replicates only in the respiratory tract. Numbers of D(b)NP(366)- and D(b)PA(224)-specific CD8(+) T cells were measured by tetramer staining at the end of the recall response, then followed sequentially in the lung, lymph nodes, spleen, blood, and other organs. The extent of clonal expansion did not reflect the sizes of the preexisting memory T cell pools. Although the high-frequency CD8(+) tetramer(+) populations in the pneumonic lung and mediastinal lymph nodes fell rapidly from peak values, the "whole mouse" virus-specific CD8(+) T cell counts decreased only 2-fold over the 4 weeks after infection, then subsided at a fairly steady rate to reach a plateau at about 2 months. The largest numbers were found throughout in the spleen, then the bone marrow. The CD8(+)D(b)NP(366)+ and CD8(+)D(b)PA(224)+ sets remained significantly enlarged for at least 4 months, declining at equivalent rates while retaining the nucleoprotein > acid polymerase immunodominance hierarchy characteristic of the earlier antigen-driven phase. Lowest levels of the CD69 "activation marker" were detected consistently on virus-specific CD8(+) T cells in the blood, then the spleen. Those in the bone marrow and liver were intermediate, and CD69(hi) T cells were very prominent in the regional lymph nodes and the nasal-associated lymphoid tissue. Any population of "resting" CD8(+) memory T cells is thus phenotypically heterogeneous, widely dispersed, and subject to broad homeostatic and local environmental effects irrespective of epitope specificity or magnitude.     

Respiratory syncytial virus and T cells: interplay between the virus and the host adaptive immune system

Respiratory syncytial virus (RSV) is a major cause of morbidity in young infants and is increasingly recognized as an important cause of serious illness/morbidity in the elderly. This agent has also been implicated both in the etiopathogenesis of asthma/airway hyperreactivity and in the exacerbation of wheezing episodes in individuals with asthma. This review deals with our current knowledge of the host adaptive immune response to RSV, focusing on the interaction of the virus with T lymphocytes. Current information on the impact of RSV infection on the function of responding CD4 (+) and, in particular, CD8 (+) T lymphocytes will be reviewed; and the potential implications of this virus/immune cell interaction on the development of RSV-induced disease in the respiratory tract will be discussed. In addition, the long-standing conundrum concerning the development of an effective vaccine against RSV will be discussed in the context of the vaccine-induced enhanced disease during RSV infection and the interplay between the virus and immune/memory T cells in the development of pulmonary injury in vaccinated individuals after the RSV infection.     

Respiratory syncytial virus-specific CD8+ memory T cell responses in elderly persons

BACKGROUND: We investigated respiratory syncytial virus (RSV)-specific CD8(+) memory T cell responses in healthy control participants (n=31) and in patients with chronic obstructive pulmonary disease (COPD) (n=9), with respect to frequency, memory phenotype, and proliferative requirements. METHODS: The properties of RSV-specific CD8(+) T cells were analyzed by use of RSV tetramers. The proliferative requirements of RSV-specific CD8(+) T cells were analyzed by culture of peripheral-blood mononuclear cells with RSV peptide in combination with distinct cytokines. RESULTS: RSV-specific CD8(+) memory T cells showed a high level of expression of CD27 and interleukin-7R alpha and a low level of expression of CCR7. In the healthy participants, the frequency of RSV tetramer(+) CD8(+) T cells was significantly lower than the frequency of influenza virus A (FLU) tetramer(+) CD8(+) T cells (P=.0001). In contrast to FLU tetramer(+) CD8(+) T cells, we could detect RSV tetramer(+) CD8(+) T cells in the subgroup of elderly healthy participants (age, > or =55 years) and in the patients with COPD only after in vitro expansion. Expanded RSV-specific T cells produced interferon- gamma and granzyme B. CONCLUSION: We provide evidence that a pool of functional RSV-specific CD8(+) memory T cells persists in the peripheral blood of healthy individuals and patients with COPD. Low numbers of RSV-specific memory T cells in the elderly and in patients with COPD may explain the increased susceptibility to RSV infection in these populations.     

Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung

BACKGROUND: We investigated CD4(+) memory T cell responses to influenza virus (FLU), respiratory syncytial virus (RSV), and nontypeable Haemophilus influenzae (NTHi). METHODS: The precursor frequencies of antigen-specific CD4(+) cells were determined by in vitro expansion of peripheral blood mononuclear cells from healthy individuals (n=9) and patients with chronic obstructive pulmonary disease (COPD; n=16). The expression of CD27 and CCR7 and the production of interferon (IFN)- gamma and interleukin-2 was measured directly ex vivo. Furthermore, the phenotypic and functional properties of CD4(+) T cells residing in the lung were analyzed and compared with those of circulating CD4(+)memory cells from the same donors (n=8). RESULTS: FLU-, RSV-, and NTHi-specific CD4(+) memory T cells circulated at low frequencies in the peripheral blood of healthy individuals and patients. RSV- and NTHi-specific CD4(+) T cells had a memory phenotype with moderate to high CD27 and CCR7 expression. In contrast to the low frequencies of circulating FLU-specific CD4(+) T cells, we found an enrichment of differentiated CD4(+) FLU-specific cells and high IFN- gamma expression in CD4(+) memory cells in lung tissue. CONCLUSION: No gross defects were found in circulating CD4(+) memory cells specific for pathogens associated with COPD. However, the large differentiated CD4(+) memory T cell pool residing in the lung may contribute to a large extent to local antiviral immunological protection.     

Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions

Although an increased frequency of CD4(+)CD8(+) T cells has been observed in the peripheral blood during viral infections, their role, function, and biologic significance are still poorly understood. Here we demonstrate that the circulating CD4(+)CD8(+) T-cell population contains mature effector memory lymphocytes specific for antigens of multiple past, latent, and high-level persistent viral infections. Upon in vitro antigenic challenge, a higher frequency of CD4(+)CD8(+) than single-positive cells displayed a T helper 1/T cytotoxic 1 (Th1/Tc1) cytokine profile and proliferated. Ex vivo, more double-positive than single-positive cells exhibited a differentiated phenotype. Accordingly, their lower T-cell receptor excision circles (TREC) content and shorter telomeres proved they had divided more frequently than single-positive cells. Consistent with expression of the tissue-homing marker CXCR3, CD4(+)CD8(+) T cells were demonstrated in situ at the site of persistent viral infection (ie, in the liver during chronic hepatitis C). Finally, a prospective analysis of hepatitis C virus (HCV) infection in a chimpanzee, the only animal model for HCV infection, showed a close correlation between the frequency of activated CD4(+)CD8(+) T cells and viral kinetics. Collectively, these findings demonstrate that peripheral CD4(+)CD8(+) T cells take part in the adaptive immune response against infectious pathogens and broaden the perception of the T-cell populations involved in antiviral immune responses.     

Location rather than CD62L phenotype is critical in the early establishment of influenza-specific CD8+ T cell memory

The rapid recall of influenza virus-specific CD8(+) T cell effector function is protective, although our understanding of T cell memory remains incomplete. Recent debate has focused particularly on the CD62L lymph node homing receptor. The present analysis shows that although functional memory can be established from both CD62L(hi) and CD62L(lo) CD8(+) T cell subsets soon after initial encounter between na?ve precursors and antigen, the optimal precursors are CD8(+)CD44(hi)CD25(lo) immune lymphocytes isolated from draining lymph nodes on day 3.5 after influenza virus infection. Analysis of primed T cells at different times after challenge indicates that the capacity to transfer memory is diminished at the peak of the primary cytotoxic T lymphocyte response, challenging speculations that the transition to memory first requires full differentiation to effector status. It seems that location rather than CD62Lhi/lo phenotype may be the more profitable focus for further dissection of the early establishment of T cell memory.     

In vivo proliferation of naïve and memory influenza-specific CD8+ T cells

The virus-specific CD8(+) T cell response has been analyzed through the development, effector, and recovery phases of primary and secondary influenza pneumonia. Apparently, most, if not all, memory T cells expressing clonotypic receptors that bind a tetrameric complex of influenza nucleoprotein (NP)(366-374) peptide+H-2D(b) (NPP) are induced to divide during the course of this localized respiratory infection. The replicative phase of the recall response ends about the time that virus can no longer be recovered from the lung, whereas some primary CD8(+)NPP(+) T cells may proliferate for a few more days. The greatly expanded population of CD8(+)NPP(+) memory T cells in the lymphoid tissue of secondarily challenged mice declines progressively in mean prevalence over the ensuing 100 days, despite the fact that at least some of these lymphocytes continue to cycle. The recall of cell-mediated immunity thus is characterized by massive proliferation of the antigen-specific CD8(+) set, whereas the extent of lymphocyte turnover in the absence of cognate peptide is variable, at a low level, and can be influenced by intercurrent infection.     

DNA-MVA vaccine protection after X4 SHIV challenge in macaques correlates with day-of-challenge antiviral CD4+ cell-mediated immunity levels and postchallenge preservation of CD4+ T cell memory

The ability of vaccines to induce immunity both in mucosal and systemic compartments may be required for prevention of HIV infection and AIDS. We compared DNA-MVA vaccination regimens adjuvanted by IL-12 DNA, administered intramuscularly and nasally or only nasally. Most of the vaccinated Rhesus macaques developed mucosal and systemic humoral and cell-mediated SHIV-specific immune responses. Stimulation of mucosal anti-Env IgA responses was limited. After rectal challenge with SHIV 89.6P, all vaccinated and naive animals became infected. However, most of the vaccinated animals showed significant control of viremia and protection from CD4(+) T cell loss and AIDS progression compared to the control animals. The levels of CD4(+) and CD8(+) T cell virus-specific responses measured on the day of challenge correlated with the level of viremia control observed later during the chronic infection. Postchallenge viremia levels inversely correlated with the preservation of SHIV-specific CD4(+)/IL-2(+) and CD8(+)/TNF-alpha(+) T cells but not with CD4(+)/IFN-gamma(+) T cells measured over time after challenge. We also found that during the early chronic infection SHIV vaccination permitted a more significant preservation of both naive and memory CD4(+) T cells compared to controls. In addition, we observed a more significant and prolonged preservation of memory CD4(+) T cells after SHIV vaccination and challenge than that observed after SIV vaccination and challenge. As the antiviral immunity stimulated by vaccination is present in the memory CD4(+) T cell subpopulations, its more limited targeting by SHIV compared to SIV may explain the better control of X4 tropic SHIV than R5 tropic SIVs by vaccination.     

Development of virus-specific CD4+ T cells on reexposure to Varicella-Zoster virus

Immunity to childhood diseases is maintained for decades by mechanisms that, at present, are still unclear. We longitudinally studied immune responses in 16 adults exposed to children experiencing varicella (chicken pox). None of the individuals showed clinical signs of infection, and varicella-zoster virus (VZV) DNA could not be detected in peripheral blood or cultured from nasopharyngeal swabs. Exposure to VZV, however, induced expansion of antigen-specific CD4(+) T cells in peripheral blood, with concomitant changes in cytotoxic CD8(+) T cells and natural killer cells. VZV-specific memory CD4(+) T cells were uniformly CD45RA(-) and enriched for CD27(-) cells. The virus-specific cells produced interferon- gamma, tumor necrosis factor- alpha, and interleukin-2. These memory responses to VZV were compared with the primary immune responses of children experiencing varicella. VZV-specific memory CD4(+) T cell responses largely resemble the primary immune response to VZV.     

CD4(+) T cell-mediated control of a gamma-herpesvirus in B cell-deficient mice is mediated by IFN-gamma

The lack of B cells and antibody does not prevent mice from dealing effectively with a pathogenic gamma-herpesvirus. Both CD4(+) and CD8(+) T cells contribute to the control of virus replication in the respiratory tract, with the depletion of either lymphocyte subset leading to increased titers in the lung. However, the further neutralization of IFN-gamma diminishes the effectiveness of the CD4(+) T cell response and causes substantially increased mortality. Experiments with bone marrow radiation chimeras indicate that the immune CD4(+) effectors operate optimally when there is the potential for direct interaction with virus-infected targets expressing MHC class II glycoproteins, suggesting that the IFN-gamma produced by these lymphocytes is functioning at short range. The numbers of latently infected cells in the spleens of carrier mice are also significantly increased by the concurrent depletion of both the CD4(+) population and IFN-gamma. These experiments raise the possibility that the defective control of intercurrent gamma-herpesvirus infections in patients with AIDS not only is due solely to the absence of helper T cells but also reflects the loss of an important set of CD4(+) effectors.     

Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination

The ability of vaccines to induce memory cytotoxic T-cell responses in the lung is crucial in stemming and treating pulmonary diseases caused by viruses and bacteria. However, most approaches to subunit vaccines produce primarily humoral and only to a lesser extent cellular immune responses. We developed a nanoparticle (NP)-based carrier that, upon delivery to the lung, specifically targets pulmonary dendritic cells, thus enhancing antigen uptake and transport to the draining lymph node; antigen coupling via a disulfide link promotes highly efficient cross-presentation after uptake, inducing potent protective mucosal and systemic CD8(+) T-cell immunity. Pulmonary immunization with NP-conjugated ovalbumin (NP-ova) with CpG induced a threefold enhancement of splenic antigen-specific CD8(+) T cells displaying increased CD107a expression and IFN-γ production compared with immunization with soluble (i.e., unconjugated) ova with CpG. This enhanced response was accompanied by a potent Th17 cytokine profile in CD4(+) T cells. After 50 d, NP-ova and CpG also led to substantial enhancements in memory CD8(+) T-cell effector functions. Importantly, pulmonary vaccination with NP-ova and CpG induced as much as 10-fold increased frequencies of antigen-specific effector CD8(+) T cells to the lung and completely protected mice from morbidity following influenza-ova infection. Here, we highlight recruitment to the lung of a long-lasting pool of protective effector memory cytotoxic T-cells by our disulfide-linked antigen-conjugated NP formulation. These results suggest the reduction-reversible NP system is a highly promising platform for vaccines specifically targeting intracellular pathogens infecting the lung.     

Immunological profile of heterosexual highly HIV-exposed uninfected individuals: predominant role of CD4 and CD8 T-cell activation

BACKGROUND: Altered T cell subset distribution patterns in uninfected individual highly exposed to human immunodeficiency virus (HIV) have been explained either as a consequence of viral exposure or as a surrogate marker of low susceptibility to infection. METHODS: Multiple genetic and immunological parameters were studied prospectively in 21 HIV-serodiscordant heterosexual couples. RESULTS: We found changes of both CD4(+) and CD8(+) T cells in highly HIV-exposed, uninfected individuals, with a lower level of naive and CD28(+) T cells and higher levels of HLA-DR(+) T cells and CD4(+) T cells expressing CCR5 and memory CD4(+) T cells than in control subjects. The changes in memory and activated T cells observed in highly HIV-exposed, uninfected partners were directly correlated with plasma viral load (PVL) of the HIV-1-infected partners, whereas changes in naive and CD4(+) CD28(+) T cells observed in highly HIV-exposed uninfected partners were inversely correlated with PVL of the HIV-1-infected partners. We were only able to detect HIV-1-specific T-cell responses in a few highly HIV-exposed uninfected partners. CONCLUSIONS: These data suggest that the peripheral immune cells of highly exposed, uninfected individuals responded according to the level of HIV exposure from the partner, even though evidence of specific HIV stimulation is rarely seen.     

Asthma death, CD8+ T cells, and viruses

Despite advances in the understanding of the pathophysiology of asthma and the availability of effective treatment, the World Health Organization estimates that asthma accounts for 1 in every 250 deaths worldwide. Viruses are associated with half of all asthma exacerbations. The immune response to viral infection may enhance preexisting airway inflammation via the release of chemokines and cytokines and local recruitment of inflammatory cells. Murine models have provided evidence for a deleterious role for CD8+ T cells in the context of respiratory viral infection. Passive transfer of respiratory syncytial virus-specific cytotoxic T lymphocytes (CTLs) to infected mice results in virus clearance, which is associated with acute and sometimes fatal pulmonary disease. Compared with control subjects, CD8+ cells appear to be preferentially sequestered in the airways of individuals with asthma during acute exacerbations. In addition, an expanded CD8+ T cell population, dominated by activated cytotoxic CD8+ lymphocytes, has been documented in biopsies from patients dying as a result of acute asthma in association with a viral infection. Undoubtedly, CD8+ CTLs are a crucial in cell-mediated immunity in response to respiratory viruses. However, it would appear that an aberrant CD8+ T cell response in the context of a viral infection may place individuals with asthma at risk for fatal asthma.     

IL-15 enhances survival and function of HIV-specific CD8+ T cells

HIV-specific CD8(+) T cells are prone to undergo apoptosis, and this may affect their ability to control HIV infection. Because CD8-mediated immune responses play a key role in controlling HIV infection, enhancing the survival and effector function of HIV-specific CD8(+) T cells may augment their ability to control HIV virus. We show here that interleukin 15 (IL-15) potently inhibits spontaneous and CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells. IL-15 inhibits apoptosis in both CD45RA(-)CD62L(-) and CD45RA(+)CD62L(-) effector memory subpopulations of these cells. Furthermore, IL-15 greatly enhances the survival of HIV-specific CD8(+) T cells in long-term cultures. Finally, IL-15 directly enhances activation, interferon gamma (IFNgamma) production, and direct ex vivo cytotoxicity of HIV-specific CD8(+) T cells. Thus, IL-15 potently enhances the survival and effector function of HIV-specific CD8(+) T cells and, therefore, may prove useful in augmenting the antiviral function of these cells.     

Intestinal double-positive CD4+CD8+ T cells of neonatal rhesus macaques are proliferating, activated memory cells and primary targets for SIVMAC251 infection

Peripheral blood and thymic double-positive (DP) CD4(+)CD8(+) T cells from neonates have been described earlier, but the function and immunophenotypic characteristics of other tissue-derived DP T cells are not clearly understood. Here, we demonstrate the functional and immunophenotypic characteristics of DP cells in 6 different tissues, including thymus from normal neonatal rhesus macaques (Macaca mulatta) between 0 and 21 days of age. In general, intestinal DP T cells of neonates have higher percentages of memory markers (CD28(+)CD95(+)CD45RA(low)CD62L(low)) and proliferation compared with single-positive (SP) CD4(+) and CD8(+) T cells. In addition, percentages of DP T cells increase and CD62L expression decreases as animals mature, suggesting that DP cells mature and proliferate with maturity and/or antigen exposure. Consistent with this, intestinal DP T cells in neonates express higher levels of CCR5 and are the primary targets in simian immunodeficiency virus (SIV) infection. Finally, DP T cells produce higher levels of cytokine in response to mitogen stimulation compared with SP CD4(+) or CD8(+) T cells. Collectively, these findings demonstrate that intestinal DP T cells of neonates are proliferating, activated memory cells and are likely involved in regulating immune responses, in contrast to immature DP T cells in the thymus.     

Decrease in hepatic CD56(+) T cells and V alpha 24(+) natural killer T cells in chronic hepatitis C viral infection

BACKGROUND/AIMS: The intrahepatic immune system is likely to play a key role in determining the outcome of hepatitis C virus (HCV) infection. The hepatic lymphocyte repertoire is characterised by high CD8/CD4 T cell ratios and large numbers of gamma delta T cells, natural killer (NK) cells, NK T cells and NK receptor-positive T cells. It is not known which of these populations contribute to immunity against HCV or immune pathology. METHODS: To explore the relative contributions of lymphocyte subpopulations, we have compared the intrahepatic lymphocyte repertoires and cytokine expression in 13 patients with mild chronic hepatitis C infection, 14 with end-stage hepatitis C cirrhosis and five histologically normal livers by flow cytometry and immunohistochemistry. RESULTS: CD4(+) T cells bearing alpha beta T cell receptors (TCR) were significantly expanded in livers with chronic HCV infection while CD56(+) alpha beta T cells and V alpha 24 TCR-positive T cells were significantly depleted. Expanded CD4(+)T cells were predominantly Th1 cells, producing interferon-gamma but not interleukin-4. CONCLUSIONS: Failure to resolve HCV infection may be due to deficient innate and/or memory immune responses, while Th1 cells may mediate immune pathology.     

Antigen burden is major determinant of human immunodeficiency virus-specific CD8+ T cell maturation state: potential implications for therapeutic immunization

The majority of untreated human immunodeficiency virus (HIV) type 1-infected individuals ultimately develop uncontrolled viremia and progressive disease. Cytotoxic T lymphocytes (CTLs) are known to play an important role in controlling HIV-1 replication, which has led to an increasing interest in augmenting conventional antiretroviral therapy with therapeutic vaccination. The successful development of a therapeutic vaccine will rely on the ability to correlate an aspect of the immune response with clinical outcome. In this study, the CD8(+) T cell maturation status of antigen-specific cells in models of well and poorly controlled virus infections were compared, to show that a memory phenotype predominates when antigen loads are absent or low. In HIV-1 infection, the emergence of memory CD8(+) T cells was found to occur only in individuals with highly suppressed viral replication for an extended duration. Such assessments of the immune response may provide a refined measure of virus control.     

Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG

Respiratory syncytial virus (RSV) is one of the leading causes of childhood hospitalization and a major health burden worldwide. Unfortunately, because of an inefficient immunological memory, RSV infection provides limited immune protection against reinfection. Furthermore, RSV can induce an inadequate Th2-type immune response that causes severe respiratory tract inflammation and obstruction. It is thought that effective RSV clearance requires the induction of balanced Th1-type immunity, involving the activation of IFN-γ-secreting cytotoxic T cells. A recognized inducer of Th1 immunity is Mycobacterium bovis bacillus Calmette–Guérin (BCG), which has been used in newborns for decades in several countries as a tuberculosis vaccine. Here, we show that immunization with recombinant BCG strains expressing RSV antigens promotes protective Th1-type immunity against RSV in mice. Activation of RSV-specific T cells producing IFN-γ and IL-2 was efficiently obtained after immunization with recombinant BCG. This type of T cell immunity was protective against RSV challenge and caused a significant reduction of inflammatory cell infiltration in the airways. Furthermore, mice immunized with recombinant BCG showed no weight loss and reduced lung viral loads. These data strongly support recombinant BCG as an efficient vaccine against RSV because of its capacity to promote protective Th1 immunity.