A role for tumor necrosis factor receptor type 1 in gut-associated lymphoid tissue development:: Genetic evidence of synergism with lymphotoxin β

Lymphotoxin alpha (LT alpha) signals via tumor necrosis factor receptors (TNFRs) as a homotrimer and via lymphotoxin beta receptor (LT beta R) as a heterotrimeric LT alpha(1)beta(2) complex. LT alpha-deficient mice lack all lymph nodes (LNs) and Peyer's patches (PPs), and yet LT beta-deficient mice and TNFR-deficient mice have cervical and mesenteric LN. We now show that mice made deficient in both LT beta and TNFR type 1 (TNFR1) lack all LNs, revealing redundancy or synergism between TNFR1 and LT beta, acting presumably via LT beta R. A complete lack of only PPs in mice heterozygous for both lt alpha and lt beta, but not lt alpha or lt beta alone, suggests a similar two-ligand phenomenon in PP development and may explain the incomplete lack of PPs seen in tnfrl(-/-) mice.