Whole body CD4 T cell census questions role of gut

Richard Jefferys, TAG

One of the most bizarre and misleading developments in HIV pathogenesis research over the past few years has been the emergence of the following statement (or variations thereof) in papers and presentations: The majority of all CD4 T cells reside in the gut. As explained in a review published several years ago by Vitaly Ganusov and Rob De Boer, there has never been any good data to support this claim. [1]

It seems to have emerged in a sort of scientific game of telephone, in which the observation that the majority of IgA-producing B-lymphocytes reside in the gut somehow got transmogrified into the majority of lymphocytes including CD4 T cells residing in the gut. Ganusov & De Boers survey of the literature – reported on the blog when the review was published – suggests that approximately 12% of lymphocytes are in the gut at any given time, not the majority. [2]

A new paper just published in the journal Blood offers compelling confirmation of this estimate by measuring CD4 T cells in the blood and tissues of rhesus macaques (both uninfected and SHIV-infected animals). [3]

The study was conducted by Michele Di Mascio and colleagues from H. Clifford Lanes laboratory at NIAID, using a technique that applies a radioactive label to CD4 T cells so that they can be visualised using single photon emission computed tomography (SPECT). Di Mascio combined this imaging approach with analyses of tissue samples from multiple body sites in order to generate estimates of the total numbers of cells and the relative contributions of different body compartments. Among the papers key findings:

1. There was a significant and close correlation between CD4 T cell numbers in lymphoid tissues and peripheral blood CD4 T cell counts. However the relationship was not linear, meaning that early declines in blood CD4 T cell counts reflected relatively small changes in CD4 T cell numbers in lymphoid tissues, but once blood CD4 T cell counts became low, further declines were paralleled by much greater loss of cells from the lymphoid tissues.

The researchers write: Based on this relationship one could extrapolate that 1) for a subject starting with 1000 CD4+ T cells/mm3 in the peripheral blood, a drop to 500 cells/mm3 is associated with approximately a 20% decrease in the number of CD4+ cells per unit mass of lymphoid tissue; 2) whereas for a subject starting with 100 CD4+ T cells/mm3, a decline to 50 cells/mm3 is associated with approximately a 45% decrease in the number of CD4+ cells per unit mass of lymphoid tissue. Thus, for subjects with low CD4+ T cell counts, changes in the number of CD4+ T cells in the blood predict larger changes in the number of CD4+ cells per unit mass of lymphoid tissues than the changes in lymphoid tissue predicted for individuals with higher CD4+ T cell counts in the peripheral blood.

2. The total body lymphocyte count is estimated to be between 1.9 and 3.5 trillion, around 4-8 fold higher than previous estimates. The researchers hypothesise that the use of a technique that requires less manipulation of tissue samples may account for the difference. This range for total body lymphocyte count is also used to estimate the proportion of lymphocytes that are in the blood: Given the above range of (1.9-3.5 trillion) lymphocytes in the body, the blood would contribute between 0.3% and 0.5% to the total pool of lymphocytes. Prior studies have generally suggested that the blood contains around 2% of total body lymphocytes.

3. The upper limit for the proportion of lymphocytes in the gut is estimated to be 15%: We observed that each gram of spleen carried at least 10-fold more CD4 cells than each gram of gut in an uninfected monkey. Given that the weight of the spleen (145g) is approximately 10 fold lower than the weight of the total gut in adult humans (1,100 to 1,500 g), it can by concluded that at the most the gut contains a number of CD4+ T cells equal to that of the spleen. Since the relative contribution of the spleen to the entire pool of lymphocytes is ?15%, then an upper limit for the relative contribution of the gut to the entire pool of lymphocytes should also be ?15%…Our results are consistent with the previously reported low number of total lymphocytes per gram of gut in adult pigs, rhesus monkeys and humans, as recently reviewed by Ganusov et al.

The study authors conclude by saying: Taken together these data suggest a need to re-evaluate current assumptions regarding the relative contribution of different tissues to the overall pool of CD4+ T cells. They acknowledge that further studies are needed to refine and increase confidence in the numbers generated, and while these are some of the best-supported estimates yet published, they do not represent the last word on the subject.

Source: TAG Basic Science Weblog. (07 May 2009) http://tagbasicscienceproject.typepad.com

References:

http://www.ncbi.nlm.nih.gov/pubmed/17964854
http://tagbasicscienceproject.typepad.com/tags_bas ic_science_vaccin/2007/10/do-most-lymphoc.html
Di Mascio M et al Non-invasive in vivo imaging of CD4 cells in SHIV infected non-human primates. Blood First Edition Paper, prepublished online May 5, 2009. DOI 10.1182/blood-2008-12-192203.
http://bloodjournal.hematologylibrary.org/cgi/content/abstract /blood-2008-12-192203v