Consider the scenario of a mouse that lacks all secondary lymphoid tissues and T cells. This mouse must co-exist with the huge biomass of microorganisms living in the gut. Can it do this? Amazingly, yes! A landmark paper by Sidonia Fagarasan and colleagues published in 2008 revealed that isolated lymphoid follicles (ILFs) in the gut can function as inductive sites for the generation of IgA-producing plasma cells in the absence of T cell help. This primordial mechanism for maintaining homeostasis with our microbiota could also explain why humans with hyper-IgM syndrome, who harbour mutations in CD40 and hence have defective B cell–T cell interactions, retain intestinal IgA responses.
At the time of this publication, my lab had been puzzling over why lymphotoxin (LT)-deficient mice have a selective deficiency in IgA. Seminal findings from Reina Mebius’ group had shown that lymphoid tissue inducer (LTi) cells are a crucial source of LTαβ that, through stimulation of LTβ receptor on stromal cells, initiates the development of lymphoid tissue anlage. Fagarasan and colleagues made the next leap in our understanding by showing that LTαβ-expressing ‘LTi-like’ cells in the adult gut interact with gut-resident stromal cells to orchestrate T cell-independent IgA production within ILFs. Not only did this paper provide an explanation for IgA deficiency in LT-deficient mice, but it also showed that interactions within ILFs facilitate the proteolytic processing of transforming growth factor-β to its active form, which functions to promote antibody class switching to IgA.
“among early studies that ushered in a new appreciation of ‘LTi-like’ cells, which we now know as innate lymphoid cells”
Fagarasan’s paper was among early studies that ushered in a new appreciation of ‘LTi-like’ cells, which we now know as innate lymphoid cells. Indeed, Peter Lane in his commentary on this paper noted: “Just as the complexity of DC biology has emerged over the last 20 years, the next decade is likely to see the dissection of diversity in LTi subpopulations.” Twelve years later that prophecy has been proved correct owing to seminal work by the Fagarasan lab and others.
Tsuji, M. et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261–271 (2008)
Mebius, R. E., Rennert, P. & Weissman, I. L. Developing lymph nodes collect CD4+CD3– LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7, 493–504 (1997)
Lane, P. J. L. The architects of B and T cell immune responses. Immunity 29, 171–172 (2008)
The author declares no competing interests.
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Gommerman, J.L. Intestinal protection without T cell help. Nat Rev Immunol 20, 275 (2020). https://doi.org/10.1038/s41577-020-0280-y