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S O U R C E : Cell
HIGHLIGHTS
- Dietary restriction promotes memory T cell accumulation in BM
- BM trophic factors and adipocytes promote memory T cell accumulation in BM
- Memory T cells display enhanced protective function during dietary restriction
SUMMARY
Mammals evolved in the face of fluctuating food availability. How the immune system adapts to transient nutritional stress remains poorly understood. Here, we show that memory T cells collapsed in secondary lymphoid organs in the context of dietary restriction (DR) but dramatically accumulated within the bone marrow (BM), where they adopted a state associated with energy conservation. This response was coordinated by glucocorticoids and associated with a profound remodeling of the BM compartment, which included an increase in T cell homing factors, erythropoiesis, and adipogenesis. Adipocytes, as well as CXCR4-CXCL12 and S1P-S1P1R interactions, contributed to enhanced T cell accumulation in BM during DR. Memory T cell homing to BM during DR was associated with enhanced protection against infections and tumors. Together, this work uncovers a fundamental host strategy to sustain and optimize immunological memory during nutritional challenges that involved a temporal and spatial reorganization of the memory pool within “safe haven” compartments.
Host survival depends on the ability to adapt to challenges in a way that sustains and protects fundamental physiological processes. Immunological memory is a cardinal feature of the adaptive immune system, which confers a survival advantage by allowing the host to rapidly and effectively control subsequent challenges. Such responses rely on the ability of memory T cells to persist long term, which can be divided into circulating and resident subsets. Circulating cells include central, effector, and peripheral memory T cells (TCM, TEM, and TPM) (Gerlach et al., 2016, Sallusto et al., 1999) that are required for body-wide immunosurveillance, whereas tissue resident memory cells (TRM) are essential for initiating and amplifying local responses (Jameson and Masopust, 2018, Mueller and Mackay, 2016). At steady state, memory T cell homeostasis is under the control of various cytokines, transcription factors, and metabolic fuels (Buck et al., 2016, Cui et al., 2015, Kaech and Cui, 2012, Pan et al., 2017, Surh and Sprent, 2008). However, these long-lived cells are faced with numerous challenges throughout the life of the host, including their persistence and maintenance of protective function during stress and reduced nutritional availability. Indeed, food accessibility was and can remain highly contingent on encounters with distinct environments and climatic conditions. Thus, mechanisms may have evolved to ensure that the host can adapt and thrive in situations where calories and nutrients are limited. Of interest, caloric restriction or dietary restriction (DR) has been shown to promote various aspects of host fitness, including the improvement of metabolic profiles, prevention of cellular aging, and reduced incidence of cancer (Nikolich-Zugich and Messaoudi, 2005, Redman et al., 2018, Robertson and Mitchell, 2013, Speakman and Mitchell, 2011). However, the consequence of DR on the memory T cell compartment remains to be addressed.
Due to the importance of memory T cells for host survival, defined strategies or compensatory mechanisms may be in place to sustain these cells in the context of nutritional challenges. Of relevance, we and others have found that white adipose tissue (WAT) is a reservoir for memory T cells (Han et al., 2017, Masopust et al., 2001). While WAT is reduced during DR, the bone marrow (BM) paradoxically shows increased adipogenesis in this context (Cawthorn et al., 2014, Devlin et al., 2010). These observations raised the possibility that an alliance between defined tissue compartments may serve the purpose of preserving immunological memory in the face of nutritional challenges.
Here, we show that DR induces a whole-body response, resulting in the collapse of circulating memory T cell populations in secondary lymphoid organs (SLOs) and blood but enhanced accumulation in BM. Such a response was associated with profound remodeling of the BM compartment, with increases in adipocytes and T cell trophic factors. The ability of memory T cells to accumulate in BM not only protected the memory pool from inhospitable conditions during DR, but also optimized their function in the face of secondary challenges. Altogether, this work uncovers a fundamental host strategy to adapt to physiological nutritional challenges, which are associated with a temporal and spatial reorganization of the memory pool within “safe haven” tissue compartments.
Memory T Cells Accumulate in the Bone Marrow during Dietary Restriction
To assess the fate of memory T cells in the context of a transient reduction in nutrition, mice were placed on DR, which involved receiving 50% of their daily food intake. This resulted in approximately 10%–15% weight loss (Figure S1A) and a reduction in fat mass (Figure S1B) after 1 week, followed by a plateau (Figures S1A and S1B). DR caused a decrease in SLO cellularity (Figure S1C), resulting in a decrease in number of antigen-experienced CD8+ and CD4+ T cells (Figures 1A, S1D, and S1E), as well as regulatory T cells (Treg), natural killer (NK) cells, and mature B cells (Figures S1D and S1F–S1H). A similar decrease was observed in blood and WAT (Figures 1A and S1E–S1H). Thus, DR is associated with a rapid and profound collapse of antigen-experienced T cells in the periphery, raising the possibility that memory T cells may redistribute to a distinct niche under these conditions.
Figure S1Memory T Cells Accumulate in BM during DR, Related to Figure 1
(A) Percentage weight change of mice on 50% DR for up to 6 weeks. (B) Weight (grams) of gonadal adipose tissue (GAT) in mice on DR. © Total hematopoietic cellularity of spl, cervical LN (cLN) and inguinal LN (iLN) after 3-4 wk of DR. (D) Gating strategy of BM populations analyzed during DR. (E) Number of CD4+ CD44+ T cells in spl, cLN, blood, GAT, and BM over time during DR. (F) Number of regulatory T cells (G) NK1.1+ cells and (H) B220high B cells in GAT, spl and BM after 5-6 wk of DR. (I) Number of B220- CD138+ plasma cells in BM after 5-6 wk of DR. Each symbol represents an individual mouse, except A, which is the mean of 5 mice. Data shows the mean, or mean ± SD, representative of at least 5 (A, D), or pooled from 2–3 (B, C, E–I) experiments with 3–5 mice per group. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001, ns; not significant. Two-tailed unpaired Student’s t test.
Figure 1Memory T Cells Accumulate in BM during DR
(A) Number of CD8+ CD44+ T cells in spleen (spl), cervical lymph node (cLN), blood, and gonadal adipose tissue (GAT) over time during 50% DR.
(B) Number of CD8+ CD44+ T cells in femur BM of mice on DR over time.
© Confocal microscopy of CD4+ (magenta) and CD8+ (yellow) T cells in BM after 3 weeks of DR.
(D) Number of CD8+ CD44+ T cells in BM from tibia, skull, thoracic vertebrate, humerus, and ilium of mice on DR for 3–6 weeks.
(E) Mice were infected and 4 weeks later put on DR for 4–6 weeks.
(F and G) (F) Number of memory CD8+ T cells in GAT, spl, and BM specific for the YopE antigen of Yersinia pseudotuberculolsis or (G) the nucleoprotein antigen of influenza A virus after 4–6 weeks of DR.
(H) Number of CD8+ CD44+ T cells in BM and spl of mice fed the indicated diet ad libitum or at 50% restriction for 3 weeks.
(I) Number of CD8+ CD44+ T cells in BM and spl of mice on DR for 3 weeks or on DR for 3 weeks then refed ad libitum for a further 1 or 3 week(s).
Each symbol represents an individual mouse. Data show the mean representative of four © or pooled from two to four experiments (A, B, D, and F–I) with two to five mice per group. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001; two-tailed unpaired Student’s t test. See also Figure S1.
In contrast to other compartments examined, antigen-experienced CD8+ and CD4+ T cells were significantly increased in BM during DR (Figures 1B, 1C, and S1E). Lymphocyte redistribution occurred by 1 week following the initiation of DR and was stable for at least 6 weeks (Figure 1B). Accumulation of antigen-experienced CD8+ T cells occurred across the entire BM compartment, with an increase of T cells observed in BM from the femur, tibia, skull, vertebrate, humerus, and ilium during DR (Figures 1B–1D). Such an increase was selective to memory T cells, as the number of Treg, NK cells, mature B cells, and plasma cells in BM was preserved during DR but not increased (Figures S1F–S1I).
To determine whether memory T cells induced following infection redistributed during DR, we tracked antigen-specific responses following an oral infection with Yersinia pseudotuberculosis ΔyopM (Yptb ΔyopM) (Han et al., 2017) or an intra-nasal infection with influenza A virus (A/PR/8/34). Following pathogen clearance and the establishment of memory (4 weeks), mice were placed on DR (Figure 1E), showing that these pathogen-specific memory CD8+ T cells were reduced in spleen and WAT but found at higher numbers in BM during DR (Figures 1F and 1G).
We next assessed whether a reduction in calories alone was responsible for memory T cell redistribution during DR or if defined nutrients played a role. To this end, we designed diets that when given at 50% restriction would contain normalized levels of vitamins and minerals (V&M), essential amino acids (EAA), or total protein. Normalizing V&M, EAA, or total protein still induced memory T cell redistribution to BM, while reducing calories alone was sufficient to drive the response (Figure 1H). Further, accumulation of memory T cells in BM during DR was reversible, with the steady-state number rapidly restored in BM and spleen upon refeeding (Figure 1I). Collectively, these results indicate that memory T cells collapse in SLO and blood but rapidly and reversibly accumulate in the BM compartment in response to a reduction in calories.
Circulating Memory T Cells Accumulate in Bone Marrow but Maintain the Ability to Recirculate during Dietary Restriction
Several memory T cell populations exist and are characterized by distinct migratory patterns and functional potential. DR induced a decrease in the memory T cell subsets found in SLO and WAT (Figure 2A). In contrast, the number of TCM and TEM was significantly increased in BM during DR, whereas T cells expressing a TRM or TPM phenotype were sustained (Figures 2B and S2A). The expression of the canonical memory markers CD127 (interleukin [IL]-7Rα), CD122 (IL-2Rβ/IL-15Rβ), CD25 (IL-2Rα), and CD62L (L-selectin), and transcription factors T-BET and EOMES, was similar between TCM and TEM from mice fed ad libitum or on DR (Figures S2B–S2G). Thus, DR preferentially promoted the accumulation of TCM and TEM in the BM.
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F O R T H E R E S T O F T H E S T U D Y , P L E A S E V I S I T T H E S O U R C E .
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