The kinetics of T regulatory cells in shock: beyond sepsis

Abstract

During the past decade, there have been an increasing number of studies investigating the precise role of T regulatory cells in human disease. First recognized for their ability to prevent autoimmunity, T regulatory cells control effector CD4⁺ and CD8⁺ T lymphocytes and innate immune cells by several different suppressive mechanisms, like cell to cell contact, secretion of inhibitory cytokines and cytolysis. This suppressive function of T regulatory cells could contribute in a similar way to the profound immune dysfunction seen in critical illness whether the latter is due to sepsis or severe injury.

Critical illness, resulting either from infection or from other pro-inflammatory insults, is associated with severe immune dysfunction. However, little is known about how different the dynamics of certain immune (especially suppressor) cell populations are depending on the type of primary insult. Hein and colleagues [1] investigated the role of naturally occurring T regulatory (Treg) cells in 43 patients admitted to the ICU with shock due to sepsis and non-sepsis related etiologies. The discriminating feature of the study is that it included most causes of shock, rather than limiting the scope to sepsis. In more detail, the authors compared the absolute numbers, percentages and kinetics of CD4⁺CD25⁺CD127^- Treg cells in 26 critically ill patients with septic shock and 17 patients with cardiogenic, hemorrhagic or toxic shock.

Naturally occurring CD4⁺CD25⁺ Treg cells comprise 5 to 10% of CD4⁺ T cells and play a pivotal role in maintaining immunologic homeostasis by inhibiting autoimmunity and controlling inflammation. Treg cells express the transcriptional regulator forkhead box p3 (Foxp3), which belongs to the forkhead DNA-binding transcription factor family, and is essential for both the development and suppressive function of Treg cells [2]. Although their exact contribution in sepsis and shock has not been completely elucidated yet, evidence from a number of studies suggests that Treg cells act as significant modulators of the innate and adaptive immune response after severe injury [3, 4].

After trauma, Treg cell activity increased and was associated with a decreased Th1 pro-inflammatory response, potentially contributing to injury-induced immunoparalysis, both in mice and in humans [5, 6]. Moreover, in sepsis, not only the percentage of Treg cells was higher than in healthy volunteers [1, 7], but their suppressive activity was enhanced as well, a phenomenon that correlated with increased expression of Foxp3 [8, 9]. One explanation for the persistence of Treg cells after injury, despite CD4⁺CD25^- and generalized lymphopenia [10], may be explained by their greater resistance to apoptosis [11]. Therefore, it is not surprising that Hein and colleagues [1] reported that the kinetics of Treg cells did not differ significantly between patients with septic and non-sepsis-related shock. Interestingly, survivors from the group of patients with septic shock had higher Treg cell counts and percentages than non-survivors, which remained consistent at all time points. Moreover, higher percentages of Treg cells were associated with lower blood arterial lactate and severity of illness score [1]. This could suggest a protective role of Treg cells in sepsis, although the study's small sample size precludes such a conclusion. It is also worth mentioning that this observation is contrary to the results published by Monneret and colleagues [7], where higher percentages of CD4⁺CD25⁺ cells were associated with worse prognosis in septic shock.

It is always very well received when information extracted from clinical studies is challenged in an experimental model. In the study by Hein and colleagues [1], Treg cell percentage increased early after polymicrobial sepsis, but depletion of CD25⁺ cells did not affect survival in their model. Data on sepsis outcome from previously published studies that used similar antibody depleting strategies have been inconclusive [8, 9, 12]. On the other hand, adoptive transfer of in vitro stimulated Treg cells protected mice from lethality in a dose-dependent manner in a polymicrobial sepsis model [13], and decreased Toll-like receptor (TLR)-2- and TLR-4- mediated pro-inflammatory responses in an experimental burn model [14]. At this point, however, a few important points need to be clarified: first, anti-CD25 antibody treatment may not have completely eliminated CD25^-/Foxp3⁺ or CD25^low/Foxp3⁺ Treg cells [15]; second, anti-CD25 treatment may also eliminate other activated cells that express CD25 [16]; and last, it may be useful to investigate whether antibody depletion, if performed later in the course of shock after the pro-inflammatory insult has amplified the regulatory activity of CD4⁺CD25⁺ Treg cells, could then potentially lead to a different outcome [3].

Even if no great variability exists between the kinetics and activity of Treg cells in different shock states, the sequence and timing of events that lead to the amplification of their suppressive function certainly need to be studied further.