Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.

Bronchus-associated lymphoid tissue (BALT) is occasionally found in the lungs of mice and humans; however, its role in respiratory immunity is unknown. Here we show that mice lacking spleen, lymph nodes and Peyer's patches generate unexpectedly robust primary B- and T-cell responses to influenza, which seem to be initiated at sites of induced BALT (iBALT). Areas of iBALT have distinct B-cell follicles and T-cell areas, and support T and B-cell proliferation. The homeostatic chemokines CXCL13 and CCL21 are expressed independently of TNFalpha and lymphotoxin at sites of iBALT formation. In addition, mice with iBALT, but lacking peripheral lymphoid organs, clear influenza infection and survive higher doses of virus than do normal mice, indicating that immune responses generated in iBALT are not only protective, but potentially less pathologic, than systemic immune responses. Thus, iBALT functions as an inducible secondary lymphoid tissue for respiratory immune responses.

Immunity to pathogens often requires both B cell-dependent humoral immune responses and T cell-dependent cellular immune responses, which cooperate to clear infectious organisms. Although CD4 + T cells clearly participate in humoral immune responses by providing help to B cells and can enhance cellular immunity by producing cytokines, the converse possibility, that B cells participate in both types of immune response, is still not widely accepted. Some early studies of B cell-deficient mice indicated that the absence of B cells adversely affected both CD4 + T cell [1][2][3][4] and CD8 + T cell responses 5,6. However, other studies showed that B cells were dispensable for the generation and maintenance of antigenspecific T cell responses7 -10. These conflicting results were further clouded by data showing that mice lacking B cells during embryonic development exhibit immunological abnormalities, including defects in Peyer's patch organogenesis11, loss of follicular dendritic cells (FDCs)12 , 13 and gp38-expressing stromal cells in the spleen14, alterations in splenic dendritic cell (DC) homeostasis15 and decreased T cell numbers in the thymus16 and spleen14. Given that many of the developmental and architectural defects observed in B cell-deficient mice are likely to influence T cell responses, it has been difficult to unambiguously assign a role for B cells in regulating cellular immune responses to either pathogens or autoantigens.The question of whether B cells have a role in cellular immune responses is now receiving renewed interest with the emergence of clinical data showing that B cell depletion is an effective treatment for several T cell-mediated autoimmune diseases Multiple Sclerosis (MS)17, Type 1 Diabetes (T1D)18 Rheumatoid Arthritis (RA)19 and others20 , 21. Indeed, studies in both humans and mice show that the clinical efficacy of B cell depletion therapy does not necessarily correlate with changes in the levels of circulating autoantibody, suggesting that B cells may contribute to autoimmunity independently of autoantibody production22 , 23 . Importantly, transient B cell depletion studies that distinguish the role of B cells during development from their roles during the course of an immune response have Given the relative effectiveness of B cell depletion by Rituximab, the drug has been tested in a wide variety of diseases. It is approved to treat non-Hodgkin's lymphoma and RA in patients with disease that is refractory to anti-tumour necrosis factor (TNF) therapy. Rituximab is also being evaluated for the treatment of other autoimmune diseases, including systemic lupus erythamatosus (SLE), type 1 diabetes, idiopathic thrombocytopenic purpura (ITP), pemphigus vulgaris (PV), mixed cryoglobulinemia vasculitis (MCV), T1D, MS and others 20 . Most of the clinical studies to date have focused on the extent of B cell depletion and clinical correlates of disease remission. Interestingly, autoantibody titres to some selfantigens declined following B cell depletion while others did not22 , 23, suggesting t...

Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19−CD38hiCD138+ subset was morphologically distinct, differentially expressed PC-associated genes and exclusively contained PCs specific for viral antigens to which the subjects had not been exposed for over 40 years. Protein sequences of measles- and mumps-specific circulating antibodies were encoded for by CD19−CD38hiCD138+ PCs in the BM. Finally, we found that CD19−CD38hiCD138+ PCs had a distinct RNA transcriptome signature and human immunoglobulin heavy chain (VH) repertoire that was relatively uncoupled from other BM PC subsets and likely represents the B cell response’s “historical record” of antigenic exposure. Thus, our studies define human LLPCs and provide a mechanism for the life-long maintenance of anti-viral antibodies in the serum.

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Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in non-lymphoid organs after local infection or inflammation. However, the initial events that promote this process remain enigmatic. Here we show that iBALT formed in murine lungs as a consequence of pulmonary inflammation during the neonatal period. Although CD4+CD3− lymphoid tissue inducer (LTi) cells were found in neonatal lungs, particularly after inflammation, iBALT was formed in mice lacking LTi cells. Instead, we found that interleukin 17 (IL-17) produced by CD4+ T cells was essential for iBALT formation. IL-17 acted by promoting the lymphotoxin-α-independent expression of CXCL13, which was important for follicle formation. These results suggest that IL-17-producing T cells are critical for the development of ectopic lymphoid tissues.

A diverse T cell repertoire is essential for a vigorous immune response to new infections, and decreasing repertoire diversity has been implicated in the age-associated decline in CD8 T cell immunity. In this study, using the well-characterized mouse infl uenza virus model, we show that although comparable numbers of CD8 T cells are elicited in the lung and lung airways of young and aged mice after de novo infection, a majority of aged mice exhibit profound shifts in epitope immunodominance and restricted diversity in the TCR repertoire of responding cells. A preferential decline in reactivity to viral epitopes with a low naive precursor frequency was observed, in some cases leading to " holes " in the T cell repertoire. These effects were also seen in young thymectomized mice, consistent with the role of the thymus in maintaining naive repertoire diversity. Furthermore, a decline in repertoire diversity generally correlated with impaired responses to heterosubtypic challenge. This study formally demonstrates in a mouse infection model that naturally occurring contraction of the naive T cell repertoire can result in impaired CD8 T cell responses to known immunodominant epitopes and decline in heterosubtypic immunity. These observations have important implications for the design of vaccine strategies for the elderly.

Cyclic ADP-ribose is believed to be an important calcium-mobilizing second messenger in invertebrate, mammalian and plant cells. CD38, the best-characterized mammalian ADP-ribosyl cyclase, is postulated to be an important source of cyclic ADP-ribose in vivo. Using CD38-deficient mice, we demonstrate that the loss of CD38 renders mice susceptible to bacterial infections due to an inability of CD38-deficient neutrophils to directionally migrate to the site of infection. Furthermore, we show that cyclic ADP-ribose can directly induce intracellular Ca++ release in neutrophils and is required for sustained extracellular Ca++ influx in neutrophils that have been stimulated by the bacterial chemoattractant, formyl-methionyl-leucyl-phenylalanine (fMLP). Finally, we demonstrate that neutrophil chemotaxis to fMLP is dependent on Ca++ mobilization mediated by cyclic ADP-ribose. Thus, CD38 controls neutrophil chemotaxis to bacterial chemoattractants through its production of cyclic ADP-ribose, and acts as a critical regulator of inflammation and innate immune responses.