Isolated Lymphoid Follicles

ILFs are relatively large lymphoid aggregates found throughout the LP, in both small intestine and colon, with the highest density in the antimesen-teric wall of the small intestine [20,42]. They are most abundant in the distal ileum [42], which maybe related to their developmental requirement for intestinal flora. ILFs are composed of a single B cell follicle and thus resemble a small PP. Their similarity to PPs is further underlined by the presence of a GC and M cells. A recent study implied that ILFs can serve as inductive sites for mucosal immune responses, especially following signals from pathogenic bacteria [43]. ILFs are composed of a large central cluster of B cells surrounded by a ring of RORyt+c-kit+IL-7Ra+ cells (see below and Fig. 1F). In addition, a large number of DCs are present in the ILF [20] (Fig. 2). Besides size and general morphology, ILFs appear postnatally [44], whereas PPs develop during late fetal life. Although both ILFs and PPs require LTpR signaling for development, ILFs, but not PPs, require LTpR signaling for maintenance through adulthood: Treatment of adult mice with LTpR-Ig eliminates ILFs, but not PPs or MLNs [44]. In addition, ILF development requires stimulation by commensal intestinal microflora [42]. Thus ILFs were absent in germ-free mice, which have small PPs [20], but ILF development was induced by re-colonization with normal flora [42]. Furthermore, ILF hyperplasia correlated with the increased commensal bacterial load in activation induced cytidine-deaminase (AID)-deficient mice that cannot class switch and therefore lack IgA. The ILF hyperplasia was abolished when bacterial load was decreased by antibiotic treatment [45]. Together, these studies suggest that ILFs form continuously throughout adult life, in response to the commensal microflora, and that RORyt+ cells are essential for their induction.

ILFs may be functionally redundant or complementary to PPs. They may contribute to the production of antigen-specific sIgA [17] or may serve as inductive sites of pathogen-specific immune responses in vivo [43]. One possibility is that ILFs form in the absence of PPs, when IgA levels are low, or in response to the microflora to supplement levels of sIgA, thus serving as a second line of defense and aiding the PP. Another possible role for ILFs is that they are responsible for the induction of sIgA against bacterial stimuli, whereas

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Fig. 1A-H RORyt+ cells act as inducers of all organized GALT in small intestinal LP. Different sized cryptopatches (CPs) (A-C) are present at the bottom of villi near the crypt areas (D, E). Cryptopatches contain large clusters of RORyt+ cells (red) surrounded by CD11c+ DCs (blue in A, B, andE and green in D). Very few B and T cells are present in CPs (C). RORyt+ cells are also present in ILFs (F) and around B cell follicles in the PP (G, H). All sections are at x40 magnification. Colors: A, B, E Red (RORy), blue (CD11c); C red (RORy), blue (CD3), green (B220); D red (RORy), blue (DAPI), green (CD11c); F, G red (RORy), blue (B220); H green (RORyt), blue (B220), red (CD11c)

Fig. 1A-H RORyt+ cells act as inducers of all organized GALT in small intestinal LP. Different sized cryptopatches (CPs) (A-C) are present at the bottom of villi near the crypt areas (D, E). Cryptopatches contain large clusters of RORyt+ cells (red) surrounded by CD11c+ DCs (blue in A, B, andE and green in D). Very few B and T cells are present in CPs (C). RORyt+ cells are also present in ILFs (F) and around B cell follicles in the PP (G, H). All sections are at x40 magnification. Colors: A, B, E Red (RORy), blue (CD11c); C red (RORy), blue (CD3), green (B220); D red (RORy), blue (DAPI), green (CD11c); F, G red (RORy), blue (B220); H green (RORyt), blue (B220), red (CD11c)

PPs and MLNs are more important in the production of antigen-specific sIgA after oral immunization [17,18,43].

Most studies point to a function of ILFs as sensors of intestinal microflora, receiving signals from the lumen and probably transmitting these signals to the mucosal immune system. Thus the close association of ILFs with DCs and RORyt+c-kit+ cells would allow ILFs to receive signals from the DCs that sample the lumen of the intestine. The presence of hundreds of organized lymphoid structures throughout the LP, as opposed to the limited number of PPs, would allow for faster and more efficient sampling and activation of local immune responses. Keeping the immune response localized would also

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Fig. 2 Cryptopatches and ILFs. Top and middle panels: Cryptopatches are small lymphoid aggregates consisting mainly of RORyt+ lymphoid tissue inducer-like cells and dendritic cells (DCs). ILFs are large aggregates that are readily detectable with DAPI staining and consist of a large B cell follicle surrounded by RORyt+ inducer-like cells and DCs. Sections were obtained from the small intestine of an adult RORyt-GFP-KI mouse. RORyt+ cells (green) and DCs (red) were stained with antibodies against GFP (Alexa 488) and CD11c (PE). Left panels: DAPI staining only. Bottom panel: Different stages of ILF development. In this model RORy+ cells in the cryptopatch receive signals from DCs and induce stromal cell production of chemokines, such as CXCL13, to recruit B cells and form ILFs. Structures intermediate between CPs and ILFs, containing small clusters of B cells, are often seen in the LP. Sections were obtained from the small intestine of a heterozygous CX3CR1-GFP-KI mouse. Staining is with anti-RORy+ Cy3 (red) and B220-APC for B cells (blue). In the first two panels CX3CR1+ DCs (green) were stained with an antibody against GFP (Alexa 488)

reduce the potential damage caused by inflammation, therefore maintaining the integrity of the intestinal barrier. Additionally, ILF-based immune responses may precede those in PPs and MLNs, which would require more time to develop because of the requirement for cell migration to and from these sites.

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