Page 35 - Science

with lymphodepleting agents (10–12), which BIOPHYSICS
induce homeostatic cytokines such as IL-7
dard lymphodepleting regimens induce sub- pHirst sour taste
drive
that
IL-15
expansion. Stan-
and
cell
stantial short- and long-term toxicity, and
immune reconstitution following such regi- channels pHound?
mens is prolonged and incomplete in many
patients (13). The results presented here Newly discovered acid channels may finally
raise the prospect that selective expansion of
tumor-specific T cells engineered to express resolve the sour taste reception mystery
orthoIL-2Rb using orthoIL-2 could eliminate
the requirement for lymphodepletion.
The ability of the orthoIL-2 system to sepa- By Craig Montell These latter substances bind to and acti-
rate the effects of IL-2 on immune effectors vate G protein–coupled receptors, which
(activated T cells or NK cells) from effects o you enjoy the tartness of apples or initiate signaling cascades that culminate
on T could also yield considerable clinical grapes? A touch of sour can be deli- with the TRPM5 (transient receptor poten-
regs
value. By engineering orthoIL-2Rb expres- cious. But, highly sour foods are re- tial cation channel subfamily M member
+
+
sion on T , but not immune effectors, one pulsive. This reaction warns against 5) channel (1). By contrast, Na and H are
regs
could selectively expand adoptively trans- consuming foods spoiled by bacte- detected by cation channels. In mammals,
ferred T for the treatment of autoimmune D rial growth, such as rancid milk. So, the low-salt sensor is an epithelial Na
+
regs
disease. In support of this, Sockolosky et al. it is no surprise that many animals have a channel (ENaC) (4). However, the H chan-
+
demonstrated that orthoIL-2 can selectively sense of sour taste. In humans, it is one of nel has been enigmatic. In the mouse, the
+
expand orthoIL-2Rb–expressing T ex vivo. five basic tastes, which also include sweet, H -sensing TRCs express a distant cousin
regs
The results also open the door for generating bitter, salty, and umami (the savory taste of TRPM5, called PKD2L1 (polycystic kid- Downloaded from
orthogonal pairs for other cytokine-cytokine induced by L-glutamate). Many recep- ney disease 2–like 1 protein) (5) (see the
receptors, such as IL-7–IL-7R, where one tors and ion channels in taste buds that figure). Type III TRCs respond to acids by
could potentially harness the desirable capac- are critical for detecting these chemicals activating a H channel that is blocked by
+
2+
ity of IL-7 to expand T cells while preventing Zn , a form of inhibition that is common
+
undesirable, potentially oncogenic, signaling to the only other known eukaryotic H
on immature B cells (14). channel, hydrogen voltage-gated channel 1
Despite the promise of this elegant sys- “Although the preponderance (Hv1) (6, 7).
tem, several issues remain. Administration of of evidence supports that Multiple sour taste receptors have been http://science.sciencemag.org/
non-native proteins poses a potential risk for proposed, including PKD2L1, acid-sensing
immunogenicity, as has occurred with recom- OTOP1 is the sour taste ion channels (ASICs), and hyperpolar-
binant proteins that mimic natural biologics receptor, behavioral analysis ization-activated cyclic nucleotide–gated
(15). Furthermore, although IL-2 signaling in (HCN) channels (1). One by one, the can-
adoptively transferred T cells is considered is needed to be certain.” didates have not stood up to experimen-
necessary and sufficient for antitumor reac- tal scrutiny. To solve the mystery of the
tivity, it remains possible that IL-2 signaling in foods are now known (1). However, a sour-sensing channel, Tu et al. cataloged
in accessory cells, such as NK cells, could con- mammalian sour taste receptor has been several dozen genes predicted to encode on March 1, 2018
tribute to the efficacy of rhIL-2 therapy and elusive. On page 1047 of this issue, Tu et proteins with multiple transmembrane
+
thus will be excluded by orthogonal signal- al. (2) reveal a previously unrecognized H - domains (indicative of a channel) that
ing. It is also possible that constitutive, high- selective channel that functions in mouse are expressed in PKD2L1-positive TRCs
level orthoIL-2Rb expression, driven by a taste receptor cells (TRCs, which occur in but not in TRCs expressing TRPM5. They
viral promoter such as that used here, might taste buds of the tongue) that are essen- introduced the candidate proteins into in
induce untoward regulatory circuits. Such is- tial for sour taste. This protein, Otopetrin1 vitro cell-expression systems, looking for a
+
sues will no doubt be investigated in depth to (OTOP1), was originally identified because H -influx current induced by extracellular
2+
further understand immune biology and to of its requirement in the vestibular system acidity and inhibited by Zn . OTOP1—with
more precisely tailor immune responses for to maintain balance and to perceive grav- 12 predicted transmembrane domains—
greater therapeutic benefits. j ity and limb orientation (3). The work by had >200,000-fold selectivity for H + over
Tu et al. not only provides a strong candi- Na + and, in contrast to Hv1, showed only
REFERENCES
1. J. T. Sockolosky et al., Science 359, 1037 (2018). date for the mammalian sour taste recep- minor voltage dependence (2). However, it
2. H. Kantarjian et al., N. Engl. J. Med. 376, 836 (2017). tor but also raises questions concerning is unresolved if OTOP1 is simply regulated
3. S. S. Neelapu et al., N. Engl. J. Med. 377, 2531 (2017). the broader roles of OTOP channels. (gated) by acid or whether there is greater
4. S. L. Maude et al., N. Engl. J. Med. 378, 439 (2018). + +
5. S. L. Maude et al., N. Engl. J. Med. 371, 1507 (2014). High concentrations of Na and H are regulatory complexity.
6. D. W. Lee et al., Blood 124, 188 (2014). perceived as salty and sour, respectively, Is OTOP1 the long-sought-after sour taste
7. R. L. White Jr. et al., Cancer 74, 3212 (1994). and are sensed by type III TRCs in our receptor? Strongly favoring this conclusion,
8. C. Krieg et al., Proc. Natl. Acad. Sci. U.S.A. 107, 11906 (2010).
9. H. Zhang et al., Nat. Med. 11, 1238 (2005). taste buds through mechanisms different the acid-activated H + conductance specific
10. R. J. Brentjens et al., Blood 118, 4817 (2011). from sugars, bitter compounds, and L-glu- to TRCs expressing the Pkd2l1 gene is virtu-
11. Y. Cui et al., Blood 114, 3831 (2009).
12. F. L. Locke et al., Mol. Ther. 25, 285 (2017). tamate, which are sensed by type II TRCs. ally eliminated in TRCs from tilted mutant
13. F. T. Hakim et al., J. Clin. Invest. 115, 930 (2005). mice, which have a missense mutation in
14. C. Shochat et al., J. Exp. Med. 208, 901 (2011). the Otop1 gene that impairs vestibular sys-
15. N. Casadevall, N. Engl. J. Med. 346, 469 (2002). Department of Molecular, Cellular, and Developmental Biology,
University of California, Santa Barbara, Santa Barbara, CA tem function. Although the preponderance
10.1126/science.aas9434 93106-9625, USA. Email: cmontell@ucsb.edu of evidence supports that OTOP1 is the sour
SCIENCE sciencemag.org 2 MARCH 2018 • VOL 359 ISSUE 6379 991
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