# Structure, function and engineering of immune cytokine receptor signaling

> **NIH NIH R37** · STANFORD UNIVERSITY · 2021 · $449,360

## Abstract

Garcia, K. Christooher
PROJECT SUMMARY:
lmmunoregulatory cytokines engage transmembrane signaling receptors in order to mediate a wide range of
functions including leukocyte proliferation, differentiation, and expansion. Most immunoregulatory cytokines
possess both redundant and distinct activities that are critical to normal immune homeostasis, but this functional
pleiotropy presents a major problem for the effective, targeted use of these cytokines as drugs. Cytokine
pleiotropy is a consequence of a small number of shared receptors, such as common gamma chain and gp130,
engaging many different cytokines, which then activate overlapping intracellular signaling pathways through a
limited set of JAK and STAT proteins. During the prior term of this award, we gained an appreciation for the
extracellular structural architectures of a spectrum of different cytokine complexes with shared receptors,
including those of IL-1, IL-2, IL-4, IL-6, IL-13, IL-17, IL-23, and IFN, which exhibited an astonishing diversity of
heterodimeric signaling geometries. In this renewal application, we focus our studies on the pleiotropic cytokines
IL-2 and IL-15, to ask how extracellular structures of the receptor-cytokine complexes influence transmembrane
signaling, intracellular activation of JAK and STAT, and subsequent in vivo function. We wish to determine if
the binding chemistry and geometry of the IL-2 and IL-15 receptor complex subunits plays a role in modulating
signaling specificity, and whether "tuning" signaling through structure-based cytokine engineering of receptor
interactions is a viable means of developing novel immunotherapeutics with enhanced efficacy, cell subset
preferences, and reduced toxicity. The overall goals of this highly collaborative proposal are: Aim 1- to determine
the biophysical basis for the functional redundancy and specificity exhibited by two "natural surrogate" ye
cytokines, IL-2 and IL-15, that act through shared signaling receptors (IL-2Rp and Ye) but private alpha-receptors;
Aim 2- to utilize structure-based protein engineering to attempt to create IL-2 variants with diverse signaling
properties and T cell subset preferences, that may be more effective immunotherapeutics as assessed by
collaborators in a variety of in vivo disease models; and Aim 3- to determine the mechanistic basis of antibody
potentiation of IL-2 activity towards distinct T cell subsets, as well as discover new potentiating antibodies that
could remodel the conformation of wild-type IL-2 and alter its biological activity. Finally, in Aim 4, we continue to
pursue structural information on how cytokine receptor intracellular segments engage Janus Kinase (JAK)
molecules, by reconstituting an entire full-length cytokine receptor transmembrane complex, bound to both
cytokine and intracellular JAK for imaging by crystallography and electron microscopy. In this fashion, by
combining structure (X-ray crystallography, Electron Microscopy, and NMR), protein engineering,
...

## Key facts

- **NIH application ID:** 10190779
- **Project number:** 5R37AI051321-19
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Kenan Christopher GARCIA
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $449,360
- **Award type:** 5
- **Project period:** 2002-04-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190779

## Citation

> US National Institutes of Health, RePORTER application 10190779, Structure, function and engineering of immune cytokine receptor signaling (5R37AI051321-19). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10190779. Licensed CC0.

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