Abstract
Sepsis survivors suffer from increased vulnerability to infections, and lymphopenia presumably contributes to this problem. The mechanisms of the recovery of memory CD4+ T cells after sepsis remain elusive. We used the cecal ligation and puncture mouse model of sepsis to study the restoration of the memory CD4+ T cells during recovery from sepsis. Then, adoptive transfer of antigen-specific naive CD4+ T cells followed by immunization and BrdU labeling were performed to trace the proliferation and migration of memory CD4+ T cells. We revealed that the bone marrow (BM) is the primary site of CD4+ memory T cell homing and proliferation after sepsis-induced lymphopenia. Of interest, BM CD4+ T cells had a higher basal proliferation rate in comparison with splenic T cells. These cells also show features of resident memory T cells yet have the capacity to migrate outside the BM niche and engraft secondary lymphoid organs. The BM niche also sustains viability and functionality of CD4+ T cells. We also identified IL-7 as the major inducer of proliferation of the BM memory CD4+ T cells and showed that recombinant IL-7 improves the recovery of these cells. Taken together, we provide data on the mechanism and location of memory CD4+ T cell proliferation during recovery from septic lymphopenia, which are of relevance in studying immunostimulatory therapies in sepsis.
Highlights
Because of a high prevalence and unacceptably high mortality, sepsis has been called a global health priority in a World Health Organization resolution [1]
By the means of adoptive transfer of OVA-specific CD4+ T cells with subsequent immunization and cecal ligation and puncture (CLP), we showed that bona fide memory helper T cells proliferate and expand in the bone marrow (BM) during the recovery phase of sepsis in an IL-7–dependent mechanism, and a fraction of these cells migrates to the periphery
Because we found that the recovery of BM CD4+ T cells depends on the local IL-7 availability, we tested whether this process can be enhanced by treatment with exogenous IL-7 (Figure 7A)
Summary
Because of a high prevalence and unacceptably high mortality, sepsis has been called a global health priority in a World Health Organization resolution [1]. Despite several reports showing trends of decreasing sepsis-associated mortality over recent years [3], other analyses reach less optimistic conclusions [4]. Surviving sepsis negatively affects the long-term health of the patient and increases the risk of later death [5]. Among many other negative outcomes, sepsis impairs the immune system, leading to both short- and long-term infectious complications [6]. A better understanding of the pathogenesis of sepsis and its impact on the patient’s immune competence are urgently needed
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