Anyone who has seen a presentation or read a review regarding the putative importance of gut CD4 T cell depletion in HIV infection will have come across statements like this: “the majority of CD4 T cells are mucosal” or “gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes in the body.” However, closer inspection reveals that such claims are not very well supported. As Reinhardt Pabst and Hermann Rothkötter wrote in a review published last year in Advances in Experimental Medicine and Biology: "It is often stated that lamina propria lymphocytes represent the largest lymphocyte pool in humans. This is not the case. Only when the number of plasma cells and in particular IgA-producing plasma cells are counted, does the lamina propria achieve such an outstanding position for plasma cells."
Now, Vitaly Ganusov and Rob De Boer from Utrecht University in the Netherlands have published an opinion piece that offers a detailed review of the topic in Trends in Immunology. They note that two observations seem to have led to the dogma that most lymphocytes reside in the gut: first is the large surface area involved (estimated to be 400m2 in one paper) and second, as referenced by Pabst and Rothkötter, studies have estimated that 80% of IgA-producing cells in mice and humans are in the gut. However, it turns out that surface area estimates include the microvilli, which do not harbor lymphocytes, and the surface area of the gut excluding microvilli is on the order of 2-10m2. Furthermore, IgA-secreting lymphocytes comprise only a small fraction of all the lymphocytes in the body. Ganusov and De Boer point out that “surprisingly, most of the widely cited literature claiming that the gut is the largest immune compartment in humans neither has information on the total number of lymphocytes nor on the distribution of B- and T-cell numbers in humans.”
Ganusov and De Boer scour the literature for studies that use data to estimate the total number of lymphocytes in the body and in the gut. They report that, based on studies in several mammalian species (including humans, macaques, pigs and mice), it appears approximately 5% of the entire body lymphocyte population resides in the lamina propria of the gut and approximately 12% of lymphocytes are found in the gut overall. The largest populations of lymphocytes are found in the lymph nodes (~41%) and spleen (~15%).
Ganusov and De Boer conclude by highlighting the fact that most immunology studies present observations in terms of cell frequencies rather than cell numbers, because calculating total numbers is far more challenging. They argue that, despite the difficulties involved, “studies estimating the number and phenotype of T and B lymphocytes in different organs of healthy humans or monkeys are desperately needed…measuring population sizes should allow for a more quantitative understanding of immunology, and it might ultimately allow for new insights into mechanisms of HIV pathogenesis.”
Trends in Immunology
Article in Press, Corrected Proof -
doi:10.1016/j.it.2007.08.009
Opinion
Do most lymphocytes in humans really reside in the gut?
Vitaly V. Ganusov and Rob J. De Boer
Available online 26 October 2007.
It is widely believed that the gut, and particularly the lamina propria (LP) of the gut, contains most of the lymphocytes in humans. The strong depletion of CD4+ T cells from the gut LP of HIV-infected patients was, therefore, suggested to be such a large, irreversible insult that it could explain HIV disease progression. However, reviewing data from different mammalian species, we found that only 5%–20% of all lymphocytes reside in the gut, and that only 1%–9% of the total lymphocyte number is located in the gut LP. Our findings suggest that spleen and lymph nodes, rather than the gut, are the largest immune compartments in mammals.
Comments