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TERM PAPER

CELL SIGNALING

ON

CELL SIGNALING IN IMMMUNOLOGY

SUBMITTED TO: SUBMITTED BY:

Mr. PRASANT NAME: ANGOM ELENA

SEC:K7802

ROLL NO.:A15

REGD:10810610
ACKNOWLEDGEMENT

I would like to express my gratitude to those who gave me the opputunity to complete my
term paper. I want to thank my department for giving me permission to commence this term
paper in the first instance to do the necessary work.

My colleagues, teachers supported me in completing my term paper in due time. I want


to thank them for all their help, support, interest and valuable hints.

Thank You

Angom Elena
INTRODUCTION

Cell signalling is part of a complex system of communication that governs basic cellular


activities and coordinates cell actions. The ability of cells to perceive and correctly respond to
their microenvironment is the basis of development, tissue repair, and immunity as well as
normal tissue homeostasis. Errors in cellular information processing are responsible for
diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling,
diseases may be treated effectively and, theoretically, artificial tissues may be created.

Many cell signals are carried by molecules that are released by one cell and move to make
contact with another cell. Endocrine signals are called hormones. Hormones are produced by
endocrine cells and they travel through the blood to reach all parts of the body. Specificity of
signaling can be controlled if only some cells can respond to a particular
hormone. Paracrine signals such as retinoic acid target only cells in the vicinity of the
emitting cell. Neurotransmitters represent another example of a paracrine signal. Some
signaling molecules can function as both a hormone and a neurotransmitter. For
example, epinephrine and norepinephrine can function as hormones when released from
the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine
can also be produced by neurons to function as a neurotransmitter within the
brain. Estrogen can be released by the ovary and function as a hormone or act locally via
paracrine or autocrine signaling. Active species of oxygen and nitric oxide can also act as
cellular messengers. This process is dubbed redox signaling.

Natural killer (NK) cells are important in the immune system in antiviral defense and tumor
surveillance. They recognize and kill stressed or infected cells that express markers of viral
infection or transformation but spare healthy cells displaying markers of normal self.
Recognition of these ligands by NK cells is mediated by cell surface receptors that fall into
two categories: activating and inhibitory. Inhibitory receptors consist of a single polypeptide
containing cytoplasmic immune receptor tyrosine-based inhibitory motifs that recruit tyrosine
phosphatases and abort signaling. Whereas activating receptors typically couple to signaling
adaptors that contain either an immune receptor tyrosine-based activation motif or a 'YXNM'
motif, where 'X' is any amino acid (such as the signaling adaptor DAP10) through
interactions specified by their transmembrane regions 3. It is generally thought that integration
of positive and negative signals from activating and inhibitory receptors determines
'downstream' signaling events. Signals emanating from activating and inhibitory receptors
determine the repertoire of NK receptors expressed on developing NK cells and regulate
effector functions such as cytotoxicity and the production of interferon-  (IFN- ) and other
inflammatory mediators in mature NK cells.

T-CELL ACTIVATION

The essential function of the T cell receptor complex is to identify specific bound antigen and
elicit a distinct and critical response. The mechanism by which a T-cell elicits this response
upon contact with its unique antigen is termed T-cell activation. There are a myriad of
molecules involved in the complex biochemical process by which this occurs which, in a
wider context, is generally termed trans-membrane signalling.

Although the specific mechanisms of activation vary slightly between different types of T
cells, the "two-signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells
occurs through the engagement of both the T cell receptor and CD28 on the T cell by
the Major histocompatibility complex peptide and B7 family members on the APC,
respectively. Both are required for production of an effective immune response; in the
absence of CD28 co-stimulation, T-cell receptor signalling alone results in anergy. The
signalling pathways downstream from both CD28 and the T cell receptor involve many
proteins.

The first signal is provided by binding of the T cell receptor to a short peptide presented by
the major histocompatibility complex (MHC) on another cell. This ensures that only a T cell
with a T Cell Receptor specific to that peptide is activated. The partner cell is usually a
professional antigen presenting cell (APC), usually a dendritic cell in the case
of naive responses, although B cells and macrophages can be important APCs. The peptides
presented to CD8+ T cells by MHC class I molecules are 8-9 amino acids in length; the
peptides presented to CD4+ cells by MHC class II molecules are longer, as the ends of the
binding cleft of the MHC class II molecule are open.

The second signal comes from co-stimulation, in which surface receptors on the APC are
induced by a relatively small number of stimuli, usually products of pathogens, but
sometimes breakdown products of cells, such as necrotic-bodies or heat-shock proteins. The
only co-stimulatory receptor expressed constitutively by naïve T cells is CD28, so co-
stimulation for these cells comes from the CD80 and CD86proteins, which together constitute
the B7 protein, on the APC. Other receptors are expressed upon activation of the T cell, such
as OX40 and ICOS, but these largely depend upon CD28 for their expression. The second
signal licenses the T cell to respond to an antigen. Without it, the T cell becomes anergic, and
it becomes more difficult for it to activate in future. This mechanism prevents inappropriate
responses to self, as self-peptides will not usually be presented with suitable co-stimulation.

CRITICAL RELATIONSHIP BETWEEN TCR SIGNALING POTENTIAL AND


TCR AFFINITY DURING THYMOCYTE SELECTION.

Whether a developing thymocyte becomes positively or negatively selected is thought to be


determined by the affinity/avidity of its TCR for MHC/peptide ligands expressed in the
thymus. Presumably, differences in affinity translate into differences in the potency of the
ensuing TCR-mediated signals, and these differences in signal strength determine the
outcome of thymocyte selection. However, there is little direct evidence establishing a
relationship between TCR-ligand affinity and signal strength during positive and negative
selection. The TCR complex contains multiple signaling motifs, known as immunoreceptor
tyrosine-based activation motifs (ITAMs) that are required for T cell activation. To examine
the effects of TCR signal strength on selection, the signaling potential of the TCR was
modified by substituting transgenic TCR zeta-chains containing either three, one, or zero
ITAMs for endogenous (3-ITAM) zeta-chain. These zeta-chain variants were then bred into
different alphabetaTCR transgenic backgrounds. We report that reductions in TCR signaling
potential have distinct effects on the selection of thymocytes expressing different TCRs, and
that the requirement for zeta-chain ITAMs critically depends upon the specificity and
apparently, affinity, of the TCR for its selecting ligand(s).

B- CELL SIGNALING AND TUMERIGENESIS

The proliferation and differentiation of lymphocytes are regulated by receptors localized on


the cell surface. Engagement of these receptors induces the activation of intracellular
signaling proteins that transmit the receptor signals to distinct targets and control the cellular
responses. The first signaling proteins to be discovered in higher organisms were the products
of oncogenes. For example, the kinases Src and Abelson (Abl) were originally identified as
oncogenes and were later characterized as important proteins for signal transduction in
various cell types, including lymphocytes. Now, as many cellular signaling molecules have
been discovered and ordered into certain pathways, we can better understand why particular
signaling proteins are associated with tumorigenesis. In this review, we discuss recent
progress in unraveling the molecular mechanisms of signaling pathways that control the
proliferation and differentiation of early B cells. We point out the concepts of auto-inhibition
and subcellular localization as crucial aspects in the regulation of B cell signaling.

B CELL DRIVE TO THE CELL CYCLE

B cell are non-dividing cells in the G 0 stage of the cell cycle. Activation drives the the resting
cell into the cell cycle, progressing through G1 to S phase, in which DNA is replicated. The
transition from G1 to S is a critical restriction point in the cell cycle. Once a cell has reached
S , it completes the cell cycle, moving through G2 and into mitosis.

Analysis of the progression of lymphocytes from G0 to S phase revealed similarities with the
parallel sequence in the fibroblast cell. These events can be grouped into two categories ,
competence signal and progression signals.

Competance signal drive the B cell from G 0 into early G1 rendering the cell competent to
receive the next level of signals.

Progression signal then drive cell from G1 into S and ultimately to cell division and
differentiation

Competance is not achieved by not one but two distinct signaling events which are
designated as signal 1 and signal 2. These signalling events are generated by different
pathways with thymus independent and thymus dependent antigens , but bth pathways
include signals generated when multivalent antigens binds and crosslinks mIg. Once the B
cell has acquired an effective competence signal in early activation , the interaction of
cytokines and possibly other ligands with B cell membrane receptors provodes progression
signals.

SIGNALING THROUGH MHC CLASS II MOLECULES BLOCKS CD95-


INDUCED APOPTOSIS

Regulation of viability and programmed cell death is of particular importance to


lymphocytes, because aberrant activation of immune responses may result in a state of
autoimmunity. The immune system is regulated to avoid the production of cells that are
autoreactive. The activation of B cells by CD40 ligation is accompanied by an increase
in expression of CD95 and sensitivity to CD95-induced apoptosis , which is important for the
elimination of autoreactive B cells (. However, B cells can be protected from CD95-mediated
apoptosis by engagement of the B cell Ag receptor (BCR),CD40, or the IL-4 receptor), and
mice transgenic for IL-4 receptor expression show enhanced autoimmunity .

Previously described mechanisms for blocking CD95 have involved  the transcriptional
activation of genes encoding antiapoptotic molecules.  BCR ligation results in the increased
production of antiapoptotic proteins such as bcl-xL, caspase 8 inhibitory protein, and
Fas apoptosis inhibitory molecule , while CD40 signaling can up-regulate bcl-xL and A20 .
Additionally, we have shown that BCR ligation leads to the immediate blocking of CD95-
mediated apoptosis in a manner independent of de novo transcription . Thus, B cells receive
different signals that may use distinct mechanisms to render them insensitive to CD95-
mediated apoptosis.

The pathway used by CD95 to rapidly induce apoptosis in cells  is initiated by the recruitment
of the adapter molecule called Fas-associated  death domain-containing protein , which in turn
binds to caspase 8 and a molecule called caspase 8-associated huge protein   . Both FADD and
caspase 8 are required for CD95-induced apoptosis . Assembly of this complex  leads to the
autocatalytic cleavage and activation of caspase 8, which is then able to directly act upon
downstream effector caspases such as caspase 3, 6, and 7 . Ligation  of chimeric receptors that
contain only caspase 8 as a cytoplasmic tail is sufficient to induce apoptosis .

A common theme linking several of the signals that counteract Fas-mediated  apoptosis in B
cells is that they are signals delivered to B  cells during the course of Ag-specific activation
events that require interactions with Th cells. Both B cell CD40 and IL-4  receptor signals are
provided by interaction with activated  T cells. However, such signals are not Ag specific, and
thus could result in proviability signals delivered nonspecifically  to B cells. We thus
wondered whether a cognate signal, such as engagement of B cell class II, could also provide
protection from Fas-mediated apoptosis, a protection that would be specific  to B cells able to
present Ag to the activated T cells. It is known that B cells respond to MHC class II ligation
by increasing their adhesiveness, resulting in a closer interaction between the  T and B cells .
Additionally MHC class II ligation induces TNF  secretion and contributes to B cell
differentiation as well as proliferation . Thus, MHC class II can  transduce signals that lead to
the functional activation of B cells. Early events stimulated by MHC class II include
the activation of protein tyrosine kinases, protein kinase C, phosphatidylinositol  3-kinase, and
elevated intracellular calcium . Ligation  of MHC class II on murine B cells also activates
adenylate cyclase and the production of cAMP .

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