KIR+ CD8+ T cells keep self-CD4+ T cells in check

Jun 09, 2022

The self/ non-self-recognition in adaptive immunity can be established both in central and peripheral tolerance. For the former, the selection processes of developing lymphocytes reduce but do not eliminate the self-recognizing clones. Two regulatory T-cells, CD4+ Treg and CD8+Treg cells (peripheral tolerance), maintain and regulate the self-recognizing clones. These are important to provide a complete TCR repertoire to fight against pathogens and may involve the mechanisms causing autoimmune diseases (1).

In two reports published in Nature and Science (2,3), Dr. Mark Davis' group identified a subset of CD8+ T cells carrying the marker KIRs (killer cell immunoglobulin-like receptor; KIR3DL1 or KIR2DL3 in humans, Klra6 in mice) that can suppress autoimmunity by killing pathogenic CD4+ effector T cells. The KIR+ CD8+ T cells (KIRT) have a similar transcription profile as the Qa-1b restricted regulatory CD8+ T cells found by Cantor's group (4). However, the activation of KIRT requires both MHC-I and non-classical MHC molecules. Interestingly, the KIRT population increased in autoimmune patients, animal models, and COVID-19 patients, and its size was directly associated with disease severity and vasculitis. The autoimmune suppressive function of KIRT during infections was further supported by the KIRT-depleted mice that exhibited more severe local inflammations after viral challenges.

Several questions remain to be solved. How do these CD8+ KIR+ T cells recognize the pathogenic CD4+ T cells in autoimmune diseases? What is the role of KIR, a negative regulator in T cell activation, in CD8+ regulatory T cells? As the authors suggested, will Ly49/KIR blockade enhance the suppressive activity of CD8+(Ly49+/KIR+) T cells? And finally, are there other cell types involved in peripheral tolerance, and how do they interact with the regulatory T cells? As we learn more about how these regulatory T cells work in the human immune system, we may develop new strategies to treat autoimmune diseases. We might be able to improve the efficiency of cancer immunotherapies.

OriGene provides the following molecular tools to study KIRT

KIRT marker KIRT activation KIRT up-regulated genes* KIRT down-regulated genes*
KIR3DL1 CD3E granzyme B (GZMB) CX3CR1 CD244 CCR7
KIR2DL3 CD28 perforin (PRF1) Helios (IKZF2) TIGIT CD27
CD8 IL2 T-bet (TBX21) KLRG1 CD28
*Differentially-expressed genes (DEGs) between KIR+CD8+ and KIR-CD8+ T cells

KIR<sup>+</sup> CD8<sup>+</sup> T cells keep self-CD4<sup>+</sup> T cells in check


1. Yu et al. Immunity. 2015 May 19;42(5):929-41. doi: 10.1016/j.immuni.2015.05.001
2. Saligrama N et al. Nature. 2019 Aug;572(7770):481-487. doi: 10.1038/s41586-019-1467-x
3. Li J et al. Science. 2022 Apr 15;376(6590):eabi9591. doi: 10.1126/science.abi9591.
4. Kim et al. Nature. 2010 September 16; 467(7313): 328–332. doi:10.1038/nature09370.