Endurance exercise diverts the balance between Th17 cells and regulatory T cells

Abstract

Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon) on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes, Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs). While interleukin (IL)-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF) β levels were significantly elevated. Treg levels in sedentary controls' decreased in vitro after incubation with athletes' post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies. Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Th17 levels increase in response to strenuous endurance exercise.

(A) Mean values of unstimulated Th17 cells, in response to endurance exercise. (B) Representative Th17 cell levels, as detected by flow cytometry: Upper panel: unstimulated Th17 cells (pre-stimulation with PMA was not used prior to detection of IL-17). Lower panel: levels of PMA-stimulated Th17 cells Pre = pre-exercise, Post = post-exercise, Recovery = 10 days post-exercise. * = statistically significant differences (p<0.05).

Figure 2. Sustained decrease in Tregs and FOXP3 levels in response to endurance exercise.

Percent change in of CD4+CD25+FoxP3+ (Tregs), from the total CD4+ lymphocytes (A) and mean fluorescence intensity (MFI) of FOXP3 within the Tregs (B) in response to endurance exercise, as analyzed by flow cytometry. (C) Representative Tregs levels, as detected by flow cytometry. Pre = pre- exercise, Post = post- exercise, Recovery = 10 days post-exercise. ** = statistically significant differences (p<0.01).

Figure 3. Endurance exercise induced changes in cytokine levels.

Shown are changes in serum levels of cortisol, IL-6, IL-10 and TGFβ (ELISA) in response to endurance exercise. Pre = pre- exercise, Post = post- exercise, Recovery = 10 days post-exercise. * = statistically significant differences (p

Figure 4. Post-race serum can induce a decrease in Tregs levels in vitro.

Shown are changes in controls' PBMNC that were incubated for 4 hours with athletes' pre-race (pre) and post-race (post) serum. Athletes post-race serum induced a significant decrease in controls Tregs levels (mean percent of Tregs 3±1.93% and 1.9±1.6% in pre- and post-race serum, respectively; p = 0.009 Student t test).

Figure 5. A model of homeostatic balance between Tregs and Th17 under endurance exercise.

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.