IMMUNOLOGY TODAY

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Glucocorticoids and immune function: unknown dimensions and new frontiers

Thomas Wilckens and Roe1 De Rijk

IMMUNO!.OGY TODAY

SEPTEMBER I997

IMMUNOLOGY 1-ODAY

thev e&c& can cccur wth endogenous GC levels and whether

they are dynamxc I” nature, srmdar to the concept mtmduced by

.Ash*rJl .-: J! ” La 7X-X mterachons

If the concept presented above applies to mature peripheral T cells,

one would expect that GCs can not only suppress but also enhance

T-cell pmhferation upon antigenic stimulation. When culhues are

prepared on chemtcally defixd media, the naturally ~ctm-mg GC

hydmcoihsone IS stbnufatmy in virtually all case+’ and even Dex

may enhance cell growth’. In light of this, it is wonii notir.g that,

rn zril), target cells for Go are “ever 100% deprived of the hormone

evz” during req, low nighttime blood levels. Of note, foetal calf

serum, rvhlch is often indiqxmsable for T-cell proliferation in tissue

cuihxe, may contatn basal levels of CG depending on the process-

q, 1.e. heat inactivation (R. BUG&, perj. commun.). In addition,

Tecent shdies have clearly demonstrated distinguishable enbanc-

ing and inhibi:ory effeds of GCs on T-cell pmlifeerahon following

anhgemc stxmdahon”. Importantly, enhancemenr of proliferation

was cell-density dependent at high cell density, GCs induced maxi-

mal proliferation during dqys 2 and 3 following stimulation, in-

stead of at day P folkwing stinulation. Fwthemxxe, GG had to be

present dmmg the initidl T-cell activation, with maximal stbnu-

la&n seen within the first 60 min follorving TCR activation. More

over, stim”laii0” was “bzTwd in a range that free bioacti\~e GG

would E&I during stress (Ia, “~0. This might fwther imply that

“1 zwo Uus phenmneno” is dependent on a dynamic GC rqonse.

Although it is not yet known whether GC-stbnulated peripheral

T-cell selection occurs 1~1 xv, some data ~pport this possibility. A

change m GC function, such as a generalized CC rsstance accot”-

panied by hypercortisoliim, results in a shii of the T-cell profile t*

wards CD-%-CD8 (Ref. 33), thus altering the basal peripheral T-cell

repertmre. Dwmg dynamic reactions the sihtahon is less clear.

However, superantigen (SAg) stimulation results in a” initial de-

crease of T cells expressing V&X- TCR in G-12 h, followed by a tmn-

sent clonal expa”sto” that peaks at day 2 and a successive donal

delehon that peaks at day 10 (Refs 34,35); GCs increase transiently

with a maximum at ‘Xl nun and return to basal levels within 12 h

during this process. Activation-induced ceU death at 14 h pwt-SAg

m@on is blocked by a GC type Ii Keptor antagonist. hn-

portantly, this antagonist not only inhibits death of puipheral

CW-CDS- T cells when ccadnmustered with SAg, but also kUIs aU

mice within 48 h; thus, from this study it is impossible to draw any

conclusion as to how the imtial GC increase would influence T-cell

reactions that might b+ see” at later stages. By conhast, if the GC a”-

tagonist is given as early as 4 h after SAg it has no effect on T-ceU

selechon 1” later stages. In addition, 1” zztro hgh-dcse GG -were

shown to we peripheral VpS- T cells hum SAg-induced death39

which again would imply a crucial role for a dynamic GC increase

during early immune reactions.

Recently, Zheng et 01.~ investigated the sign& that contribute to

penpheral T-cell selection following immunization and a secondary

SAg- or Dex treahnent in peripheral Iymphoid tissue. This study

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egative signaling in B cells: SHIP Grbs She

Susheela Tridandapani, Todd Kelley, Damon Cooney, Madhura Pradhan and K. Ma& Coggeshall

duces positive signaling events that result

in pmliferation and sarehan of soluble

antigen-specific Ig. The activation pmclzss

is regxdated at several IeveIs, in&ding the

interaction of B 4s with helper T c&s,

as well as the fornation and _cretion of

lymphokines that promote B-cell pmIifer-

ation and differentiation into Ig-secreting

c&I or memory B &Is. Siirly, secreted,

dntigen-specitic Ig plays a” important role

Negotiue sigtznlr~~g irz B cells IS

rrritinfed by/ cc-crosslinking of rlic mtrgtw receptor md the Fey

receptor, resultrq in ces_dio,r of

B-celi sipfiq tmfzfs ma?, ii1

twn, hrhibiting B-cell prolifemtim od mtibody secretion. Here, LI

cornpeltfrve role 1s proposed for

SHIP irr blocking the ivteructior; of

She with the GrbZ-Sos complex of

proteins thnt lend to Rm

flctiitntiorz I)I B cells.

~II the regxdahon of B-cell aclivahon: expwinwnts indicate that it

renders B 4s less responsive to anhgen-triggered xtivation and

subsequent secretion of “ascent Ig (reviewed in Ref. I). This sup

pressive effect of soluble Ig has been termed negative signahng.

Eariy studies on “egahve qnaIing by PhdIips and PXIVZ-

demonstrated that soluble, suppressive Ig must bind specific

antigen and bear a” intact Fc domain. The observation that the

suppressive effect of soluble Ig was blodced by neutralizing anti-Fc-

receptor antibodies and by protein A (Ref. 5) established a role for

the Fq receptor (F&II) in negative signaling. These hndmgs lend

support to a model of negative signaling in which the BCR 1s C(F

cmsslinked with FqRII by miuble, anhgn-sp+xIftc Ig to suppress

antibody pmduction.

Co-cmssIIIng of the BCR and FqRII probably occurs in D;U~

when secreted antigen-specific or anti-idiotyprc Ig crosslinks F&II

and the antigen-bound BCR, implying that negahve signaling is a

physiological pmcess that serves to prevent excess Ig production.

Positive signaling

This IS supported by studies on rheumatoid

arthritis in which negative signaling is po-

te”tiaIIy blocked by an autoimmune anti-Fc

antibodyh and on FcyRII-deficient mice,

which exhl%it an increase in antigenqwxific

IgG anhMi&. While the effects and bn-

portance of negative sigttafing are dear, its

biochtical basis is not well understood. Thii arti& wiiI first describe key events in positive signaling and then outline a mecha-

nistic model of negative qnaling that in-

ccqxxates exiting new findings into the

b&y of existing k”owh?dge.

Following datting, anhgen receptors of lymphocytes activate

several protein tymsine Iunases WTKs), SpecificaIIy those of the Src

and 7AP-7O/Syk fzmihs Once activated, these enzymes phos-

pnorytate several pmteins, which **en ass&ate n”ncovaIentIy via

interactions of src-homology 2 (SH2). phosphotyrosine-bmdiig

WIW, SH3 and plecksbin-homology (PHJ domain&‘“. PTK sub-

strates t” lymphocytes include pmte’ti with a consened sequence of

a”li”o aads know” as the i”l”“moreceptor ty”al&ased activation

mobf (ITAM) CR& ll-13). found in signaling subunits of antigen tp

ceptas. When phosphorylated on k-y tymsine resrdues, the ITAM ap-

pears to act as a scat%Id for a multilayered assembly of signaling pm

te”x that activate sawaI biochemical pathways, cubninating in the

inductmn of “ascent gene expressIon and entry into the c&I cyde.

The SH2domain-contaiiing adaptor pmt.zin She is among the

sgxaling proteins that are found directly or indirectIy complrxed

with ITAMS (Refs M-17). Although details of Ras activahon in BceIIs

P i: 1‘,*=“011 11