Glucocorticoids limit acute lung inflammation in concert ...
Glucocorticoids and immune function: unknown dimensions and new frontiers
-
Upload
thomas-wilckens -
Category
Documents
-
view
216 -
download
0
Transcript of Glucocorticoids and immune function: unknown dimensions and new frontiers
IMMUNOLOGY TODAY
j P / b
; il I d
! d
/ h
:n c
’ t
Glucocorticoids and immune function: unknown dimensions and new frontiers
Thomas Wilckens and Roe1 De Rijk
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
IMMUNOLOGY Tf)DAY
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