In a murine tuberculosis model, the absence of homeostatic chemokines delays granuloma formation and protective immunity.
Mycobacterium tuberculosis infection (Mtb) results in the generation of protective cellular immunity and formation of granulomatous structures in the lung. CXCL13, CCL21, and CCL19 are constitutively expressed in the secondary lymphoid organs and play a dominant role in the homing of lymphocytes and dendritic cells. Although it is known that dendritic cell transport of Mtb from the lung to the draining lymph node is dependent on CCL19/CCL21, we show in this study that CCL19/CCL21 is also important for the accumulation of Ag-specific IFN-gamma-producing T cells in the lung, development of the granuloma, and control of mycobacteria. Importantly, we also show that CXCL13 is not required for generation of IFN-gamma responses, but is essential for the spatial arrangement of lymphocytes within granulomas, optimal activation of phagocytes, and subsequent control of mycobacterial growth. Furthermore, we show that these chemokines are also induced in the lung during the early immune responses following pulmonary Mtb infection. These results demonstrate that homeostatic chemokines perform distinct functions that cooperate to mediate effective expression of immunity against Mtb infection.
Khader
Shabaana A
SA
Trudeau Institute, Saranac Lake, NY 12983, USA.
Rangel-Moreno
Javier
J
Fountain
Jeffrey J
JJ
Martino
Cynthia A
CA
Reiley
William W
WW
Pearl
John E
JE
Winslow
Gary M
GM
Woodland
David L
DL
Randall
Troy D
TD
Cooper
Andrea M
AM
D000818:Animals; D054415:Chemokine CCL19 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D054421:Chemokine CCL21 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D054382:Chemokine CXCL13 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D006099:Granuloma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007111:Immunity, Cellular / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000473:pathology
C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse