A fundamental tenet of immunology is that primary adaptive immune responses are initiated in secondary lymphoid organs, such as lymph nodes, Peyer's patches or spleen 1–3 . These lymphoid organs are organ-ized to recruit naive lymphocytes from the blood and to promote their interaction with activated antigen-presenting cells from surrounding tissues 1 . Once lymphocytes have been activated and clonally expanded in centralized lymphoid organs, the resulting effector cells localize to the infected or inflamed tissues and perform their effector functions 4 . For example, B and T cells responding to influenza virus are first detected in the lymph nodes that drain the respiratory tract, and are only later found in the lung 5 . Consistent with an essential role for lymphoid organs in primary immune responses, splenectomized lymphotoxin-α-null (Lta –/–) mice 6,7 or alymphoplastic (aly/aly, also known as Map3k14 –/–) mice 8,9 — which lack spleen, lymph nodes and Peyer's patches — are unable to generate primary immune responses to a variety of pathogens 10 , anti-gens 11 and allografts 12 . However, Lta −/− mice infected with respiratory viruses are capable of generating antigen-specific B and T cells 13,14 , albeit with delayed kinetics, suggesting that lymphocytes can also be primed in non-lymphoid tissues. Consistent with this idea, the bone marrow seems to function as an alternative site of lymphocyte priming to systemic antigens when lymph nodes are unavailable 15,16 . Another tissue that could facilitate primary immune responses to respiratory infections is the BALT 17 . Although the presence of BALT in mouse and human lungs is controversial, there are reports that infection or inflammation triggers the organization of lymphoid structures in the lungs of both species 18–21 . These structures do not fit the classical defi-nition of BALT, as they are not formed independently of antigen 22,23 . Because inducible BALT (iBALT) appears in the lung only after infection or inflammation, it is generally assumed that iBALT is simply an accumulation of effector cells that were initially primed in conven-tional lymphoid organs; however, it is also possible that inflammatory responses directly trigger the neo-formation of iBALT, which promotes the recruitment, priming and expansion of antigen-specific lymphocytes in situ. Thus, iBALT may functionally replace conven-tional lymphoid organs in respiratory immune responses. RESULTS Respiratory immunity in the absence of lymphoid organs To determine whether CD8 + T cells could be primed in the absence of conventional lymphoid organs, we generated bone marrow chimeric mice lacking lymphoid organs or LTα (Supplementary Fig. 1 online). These chimeras include wild-type (WT) mice, which possess all lymphoid organs and are populated with Lta +/+ cells; lymphotoxin chimeric (LTCh) mice, which contain all lymphoid organs and are populated with Lta –/– cells; spleen-, lymph node– and Peyer's patch–deficient (SLP) mice, which lack lymphoid organs and are pop-ulated with Lta +/+ cells; lymphotoxin knockout (LTKO) mice, which lack lymph nodes and Peyer's patches and are populated with Lta −/− cells; and, finally, splenectomized LTKO (LTKO-S) mice, which lack lymphoid organs and are populated with Lta –/– cells. After reconstitu-tion, we infected the chimeric mice with influenza and followed influenza-specific CD8 + T cells in the lungs. Although influenza nucle-oprotein (NP)-specific CD8 + cells were observed in the lungs of WT, LTCh and SLP chimeric mice by day 7 (Fig. 1a), the appearance of NP-specific CD8 + cells was delayed until after day 9 in LTKO mice, and was even further delayed in LTKO-S mice. Despite the delayed appearance of NP-specific CD8 + cells in LTKO and LTKO-S mice, the total number of these cells in the lungs eventually reached almost wild-type levels (Fig. 1b).