TCR and Activating NKRs The TCR Primacy Rule

Effector CTLs, although they can express a broad panoply of NKRs, usually lack NKRs that signal through a immunomodulatory tyrosine-based activating motif (ITAM) (Table 1). These ITAMs can recruit kinases from the ZAP70/Syk family and induce alone full cellular activation. Instead, the NKRs expressed by CTLs are characterized by their capacity to modulate, positively or negatively, TCR activation. This ensures that T cell activation remains under the control of the TCR (the TCR primacy rule). For example, NKp46 protein (Moretta and Moretta 2004; Pessino et al. 1998), which associates with CD3Z and therefore could be potentially expressed on the cell surface of CTL, is not present in CTLs, including in intracellular compartments (unpublished data). Similarly, NKG2C protein is absent in normal conditions, even though transcripts are detected (Jabri et al. 2002 and unpublished data). In addition, CTLs do not express transcripts of the ITAM-bearing adaptor

Gene

Receptor

Adaptor

Function

Ligand

CTL expression

KLRC2

NKG2C

DAP12

Activator

HLA-E

No

KLRC3

NKG2E

?

?

HLA-E

?

KLRC3

NKG2H

DAP12?

?

HLA-E?

?

KLRC4

NKG2F

DAP12?

?

?

?

KLRK1

NKG2D

DAP10

Costimulation/cytotoxicity

MICA/B,ULBP1,2,3,4

Yes

KLRC1

NKG2A/B

None

Inhibitor

HLA-E

Yes

KIR2DS (1-

-5)

CD158 (g,h,l,j),nkat7

DAP12

Activator

HLA-C?

No

KIR3DS1

CD158e2

DAP12?

Activator

?

No

KIR2DL (1-

-5)

CD158 (a,b1,b2,d,f)

None

Inhibitor

HLA-C

Yes

KIR3DL (1-

-3)

CD158 (k,z,e1)

None

Inhibitor

HLA-A?

Yes

NCR3

NKp30

CD3Z/FceR1y

Activator

?

No

NCR2

NKp44

DAP12

Activator

?

No

NCR1

NKp46

CD3Z/FceR1y

Activator

?

No

NKR-P1A

CD161

?

Costimulation?

?

Yes

CD244

2B4

SAP

Costimulation?

CD48

Yes

CD226

DNAM-1

?

Costimulation

CD112,CD155

Yes

CD96

TACTILE

?

Costimulation

CD155

Yes

LILRB1

ILT2/LIR-1

None

Inhibitor

HLA A,B,C,E,F,G, CMV UL18

Yes

molecule DAP12 (also called KARAP; Olcese et al. 1997), which is required for the expression of NKG2C (Lanier et al. 1998) and NKp44 (Moretta and Moretta 2004; Vitale et al. 1998). Furthermore, even when DAP12 transcripts are induced in T cells in pathological conditions, their presence does not signify that DAP12 protein is expressed, suggesting that DAP12 is also regulated at the translational level. Altogether, these observations suggest that there is a transcriptional and translational regulatory network, involving probably also epigenetic modifications (Uhrberg 2005), that prevents the expression of NKRs associated with ITAM-bearing adaptor molecules in T cells.

Some important exceptions to the TCR primacy rule, however, have emerged. For example during CMV infection CTLs were reported to express surface NKG2C, and similar observations were obtained in conditions of chronic T cell activation in vitro (Ortega et al. 2004) or inflammation in vivo (Guma et al. 2004 and unpublished data). These changes, which may effectively convert the CTL into an NK cell, have major physiopathological implications that are discussed later. Although they could transiently benefit the host in case of infection, they are detrimental in the case of chronic inflammation and may lead to severe immunopathology, as suggested in celiac disease.

Why Gluten Free

Why Gluten Free

What Is The Gluten Free Diet And What You Need To Know Before You Try It. You may have heard the term gluten free, and you may even have a general idea as to what it means to eat a gluten free diet. Most people believe this type of diet is a curse for those who simply cannot tolerate the protein known as gluten, as they will never be able to eat any food that contains wheat, rye, barley, malts, or triticale.

Get My Free Ebook


Post a comment