The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3

Murali Janakiram, Urvi A. Shah, Weifeng Liu, Aimin Zhao, Mark P. Schoenberg, Xingxing Zang

Research output: Contribution to journalReview articlepeer-review

178 Scopus citations


The B7-CD28 family of ligands and receptors play important roles in T-cell co-stimulation and co-inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7-H3 [CD276], B7x [B7-H4/B7S1], and HHLA2 [B7H7/B7-H5]/TMIGD2 [IGPR-1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7-H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection. Various immunotherapeutical approaches are emerging including antagonistic monoclonal antibodies and agonistic fusion proteins to inhibit or potentiate these molecules and pathways in cancers and autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)26-39
Number of pages14
JournalImmunological Reviews
Issue number1
StatePublished - Mar 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
MJ is supported by AMC grant UM1CA121947. Research in the Zang lab is supported by NIH R01CA175495 and R01DK100525, DOD Established Investigator Idea Development Award PC131008, Pfizer CTI, Hengrui Medicine Co., and Irma T. Hirschl/Monique Weill-Caulier Trust (to X. Zang).

Publisher Copyright:
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd


  • B7-H3
  • B7x
  • HHLA2
  • TMIGD2
  • immune checkpoint
  • immunotherapy


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