t Cells & Autoimmunity, s3

8/16/2019 t Cells & Autoimmunity, s3

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In the midline of the body, above theheart, is made up of several lobules

Cortex : only immature thymocytes + scattered M ϕ. Medulla : more mature

thymocytes, along with DCs and M ϕoes !ri"atna Dachlan #$%$

&'aneway C(, #$$%)Imm.biol. III ch *

The cellular organization of the human thymus


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one marrow from nude mice can restore cells to scid mice

hymic epithelial cells from scid mice caninduce the maturation of cells in nude mice

The thymus provides the essential microenvironment for T-cell development

oes !ri"atna Dachlan #$%$ &'aneway C(, #$$%)


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Most developing T cells die inthe thymus

-arliest cells : in the subcapsular region. !roliferative and mature cells &doublepositive thymocytes) into the thymic cortex. /nly mature single positive cells in themedulla leave the thymus and enter the blood stream

&'aneway C(, #$$%)oes !ri"atna Dachlan #$%$


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Double positive thymocytes :01 cells proceeds through stages whereboth CD2 and CD3 are expressed by thesame cell

Most thymocytes &45*6) die within thethymus after becoming small double

positive cells

(fter maturation, single positivethymocytes are exported from the thymusas a mature single positive CD2 or CD3 cells

oes !ri"atna Dachlan #$%$ &'aneway C(, #$$%)


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7tages of 01 cell developmentwith

cell receptor gene rearrangementand expression of cell surface proteins

&'aneway C(, #$$%)oes !ri"atna Dachlan #$%$


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Cellular proteins that to be importantfor early cell development

&'aneway C(, #$$%)& oes !ri"atna Dachlan #$%$)


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MHC & TCR

MHC8 Imprinting of self-MHC restriction

and tolerance to self on themature T-cell repertoire occurs

during thymocyte development8 In the thymus, MHC moleculesinstruct maturing T-cell how todiscriminate etween self andnon-self antigens

8 In addition to playing a !ey role

in shaping the peripheral T-cellrepertoire, MHC moleculespresent cognate antigenicmolecules, including self-antigens, to mature T cells inthe periphery

TCR8 "hereas thymocytes

e#pressing T-cell receptors$TCRs% recogni ing self-

antigen'MHC with higha(nity perish $ a process alcoreferred to as negativeselection%,

8 Those e#pressing low a(nity TCRs $for the same comple#%di)erentiate into the mature Tcells that populate theperipheral lymphoid organs

& ang ang9 7antamaria, #$$ )& oes !ri"atna Dachlan #$%%)


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THE AVIDITY M DE! " THYMI# $ %ITIVE A&D &E'ATIVE%E!E#TI &

&;oitt I, ch %#, #$$%)oes !ri"atna Dachlan #$%$


9/21

$ %ITIVE %E!E#TI &

Thymicepithelial cell

#D() #D*) thymocyte

#D(

#D*

#lass IIMH#

!o+- affinity,avidity recognition of peptide-MH# comple on

thymic epithelial cells

#D(

Mature#D() #D*- thymocyte

.es/ue fromprogrammedcell death

#onversion to

single positive

& oes !ri"atna Dachlan, #$%%)

&( (7, et al.,#$%$)

0


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!A#1 " $ %ITIVE %E!E#TI &

Thymicepithelial cell

#D() #D*) thymocyte

#D(

#D*

#lass IIMH#

"ailure to recognize peptide-MH#comple on thymic epithelial cells

#D(

& oes !ri"atna Dachlan, #$%%)

&( (7, et al.,#$%$)

Apoptoticcell death

0

0


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&E'ATIVE %E!E#TI &

Thymic A$#

#D() #D*) thymocyte

#D(

#D*#lass IIMH#

High- avidity recognition of peptide-MH#comple es on thymic epithelial cells

#D(

& oes !ri"atna Dachlan, #$%%) &( (7, et al.,#$%$)

Apoptoticcell death

#D(

0

0


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T C*++ ./ 0T1IMM0.IT2 $3%

$2ang-2ang et al4, 5667,choes !ri"atna Dachlan #$%$


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T C*++ ./ 0T1IMM0.IT2 $5%

$2ang-2ang et al4, 5667,ch 2oes 9ri:atna /achlan


15/21

T C*++ ./ 0T1IMM0.IT2$;%

$2ang-2ang et al4, 5667,ch 2oes 9ri:atna /achlan


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T C*++ ./0T1IMM0.IT2 $


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R*=0+ T1R2 T C*++ and0T1IMM0.IT2 $3%

8 *volutionarily spea!ing, T regs li!ely arose out of theimmune system>s need to control the magnitude ofin?ammatory reactions against micro ial infections, toprevent collateral damage to healthy, noninfected tissue

8 /isruption of the delicate alance that e#ist among allthese cell types of the adaptive immune system $inhealth% thus has the potential to cause autoimmunity,which, y de@nition, results from a loss of tolerance toself

8 Aecause of the central role that T cells play in adaptiveimmune responses, it is not surprising that they, too,play a fundamental role in most, if not all, autoimmunedisorders, including, those mediated y autoanti odies

& ang ang9 7antamaria, #$$ )& oes !ri"atna Dachlan #$%%)


18/21


19/21

$2oes 9ri:atna /achlan

5633%

Ch 5, #$$ : p%%5 %=%


20/21

&>orc?yns@i ;.,%555)

! %% 9" %E!"-T !E.AE

$2oes 9ri:atna /achlan


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%ignaling A8normalities in T cells and Autoimmune Diseases

7ome have a genetic basis9 others are induced by stressing environmentand thus, could be potentially reversible.

& lasini, ;odrigue?, #$$A)

Molecular (utoimmunity B Moncef ouali$2oes 9ri:atna /achlan

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t Cells & Autoimmunity, s3